ES2361403T3 - QUINAZOLINONE MODULATORS OF NUCLEAR RECEPTORS. - Google Patents

Abstract

Compounds, pharmaceutical compositions and methods for modulating the activity of nuclear receptors are provided. In particular, quinazolinones are provided for modulating the activity of farnesoid X receptor (FXR) and/or orphan nuclear receptors.

Description

FIELD OF THE INVENTION

Quinazolinones, compositions containing quinazolinones and methods for modulating the activity of nuclear receptors using quinazolinones are provided. In particular, quinazolinones are provided to modulate the activity of FXR and orphan nuclear receptors. BACKGROUND OF THE INVENTION Nuclear receptors

Nuclear receptors are a superfamily of regulatory proteins that are structurally and functionally related and are receptors for, for example, steroids, retinoids, vitamin D and thyroid hormones (see, for example, Evans (1988) Science 240: 889-895). These proteins bind to cis-acting elements in promoters of their target genes and modulate gene expression in response to ligands for receptors.

Nuclear receptors can be classified based on their DNA binding properties (see, for example, Evans, supra and Glass (1994) Endocr. Rev. 15: 391-407). For example, a class of nuclear receptors includes glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors that bind in the form of homodimers to hormone response elements (HRE) organized as inverted repeats (see, for example, Glass, supra ). A second class of receptors, including those activated by retinoic acid, thyroid hormone, vitamin D3, peroxisome fatty acids / proliferadotes (i.e., the peroxisome proliferator-activated receptor (PPAR)) and ecdysone, bind HRE in form of heterodimers with a common partner, the X retinoid receptors (i.e., RXR, also known as the 9-cis retinoic acid receptors; see, for example, Levin et al. (1992) Nature 355: 359-361 and Heyman et al. (1992) Cell 68: 397-406).

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RXRs are unique among nuclear receptors because they bind to DNA in the form of a homodimer and are necessary as a heterodimeric partner for several additional nuclear receptors to bind to DNA (see, for example, Mangelsdorf et al. (1995) Cell 83: 841 -850). The last receptors, called a class II nuclear receptor superfamily, include many that are established or involved as important regulators of gene expression. There are three RXR genes (see, for example, Mangelsdorf et al. (1992) Genes Dev. 6: 329-344), which encode RXR, , and , all of which are capable of heterodimerizing with any of the receptors of class II, although there appear to be preferences for different subtypes of RXR for companion receptors in vivo (see, for example, Chiba et al. (1997) Mol. Cell. Biol. 17: 3013-3020). In the adult liver, RXR is the most abundant of the three RXR (see, for example, Mangelsdorf et al. (1992) Genes Dev. 6: 329-344), suggesting that it may have a notable role in functions liver diseases that involve regulation by class II nuclear receptors. See also, Wan et al. (2000) Mol. Cell Biol. 20: 4436-4444. Orphan Nuclear Receivers

The nuclear protein receptor superfamily includes nuclear receptors for which the ligand is known and those lacking known ligands. Nuclear receptors that are in the last category are known as orphan nuclear receptors. The search for activators for orphan receptors has led to the discovery of previously unknown signaling pathways (see, for example, Levin et al., (1992), supra and Heyman et al., (1992), supra). For example, it has been reported that bile acids, which are involved in physiological processes such as cholesterol catabolism, are ligands for FXR (infra).

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As it is known that intermediary metabolism products act as transcriptional regulators in bacteria and yeasts, such molecules can serve similar functions in higher organisms (see, for example, Tomkins (1975) Science 189: 760-763 and O'Malley (1989) Endocrinology 125: 1119-1120). For example, a biosynthetic pathway in higher eukaryotes is the mevalonate pathway, which leads to the synthesis of cholesterol, acids

biliary, retinoid, farnesylated.

porphyrin, vitamin  Dolicol D hormone  ubiquinone steroids  carotenoids, and proteins

FXR

FXR (originally isolated as RIP14 (protein 14 that interacts with the X retinoid receptor), see, for example, Seol et al. (1995) Mol. Endocrinol. 9: 72-85) is a member of the hormonal receptor superfamily nuclear and is expressed primarily in the liver, kidney and intestine (see, for example, Seol et al., supra and Forman et al. (1995) Cell 81: 687-693). It works as a heterodimer with the X retinoid receptor (RXR) and binds to response elements in promoters of target genes to regulate gene transcription. The FXR-RXR heterodimer binds with the highest affinity to an inverted repeat response element-1 (IR-1), in which the consensus receptor binding hexamers are separated by a nucleotide. FXR is part of an interrelated process, because FXR is activated by bile acids (the end product of cholesterol metabolism) (see, for example, Makishima et al. (1999) Science 284: 1362-1365, Parks et al. ( 1999) Science 284: 1365-1368, Wang et al. (1999) Mol. Cell. 3: 543-553), which serves to inhibit cholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem. 275: 39313-39317. Nuclear receptors and diseases

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The activity of nuclear receptors, including the activity of FXR and / or orphan nuclear receptors has been implicated in a variety of diseases and disorders including, but not limited to, hypercholesterolemia, and complications thereof, including, but not limited to, coronary artery disease, pectoral angina, carotid arteriopathy, strokes, cerebral arteriosclerosis and xanthoma, (see, for example, International Patent Application Publication No. WO 00/57915), osteoporosis and vitamin deficiency (see, for example, U.S. Patent No. 6,316,5103), hyperlipoproteinemia (see, for example, International Patent Application Publication No. WO 01/60818), hypertriglyceridemia, lipodystrophy, peripheral occlusive disease, ischemic stroke, hyperglycemia and diabetes mellitus (see, for example, International Patent Application Publication No. WO 01/82917), resistance-related disorders Insulin insulin including the group of pathologies, conditions or disorders that make up "X syndrome" such as glucose intolerance, an increase in the level of triglycerides in plasma and a decrease in high density lipoprotein cholesterol concentrations, hypertension, hyperuricemia, smaller and denser low density lipoprotein particles, and higher circulatory levels of plasminogen activator inhibitor-1, atherosclerosis and gallstones (see, for example, International Patent Application Publication No. WO 00 / 37077), disorders of the skin and mucous membranes (see, for example, United States Patents No. 6,184,215 and 6,187,814, and International Patent Application Publication No. WO 98/32444), obesity, acne (see, for example, International Patent Application Publication No. WO 00/49992), and cancer, Parkinson's disease and Alzheimer's disease (see, for example , International Patent Application Publication No. WO 00/17334). The activity of nuclear receptors, including FXR and / or orphan nuclear receptors, has been implicated in physiological processes that include, but are not limited to, biosynthesis of bile acids, cholesterol metabolism or catabolism, and modulation of transcription of the 7-hydroxylase (CYP7A1) cholesterol gene (see, for example, Chiang et al. (2000) J. Biol. Chem. 275: 10918-10924), HDL metabolism (see, for example, Urizar et al. (2000) J. Biol. Chem. 275: 3931339317), hyperlipidemia, cholestasis, and increased cholesterol secretion and increased expression of the ATP-binding cassette transporter protein (ABC1) (see, for example, application publication of International Patent No. WO 00/78972). WO 01/98278 refers to quinazolinone derivatives useful in the treatment of cell proliferative diseases.

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Therefore, there is a need for compounds, compositions and methods to modulate the activity of nuclear receptors, including FXR and / or orphan nuclear receptors. Such compounds are useful in the treatment, prevention, or improvement of one or more symptoms of diseases or disorders in which the activity of nuclear receptors is involved. The problem of the present invention is solved based on claims 1 to 34. SUMMARY OF THE INVENTION

Compounds are provided for use in compositions and methods to modulate the activity of nuclear receptors. In particular, compounds are provided for use in compositions and methods for modulating the farnesoid X receptor (FXR) and / or orphan nuclear receptors. In certain embodiments, the compounds are quinazolinones. In one embodiment, the compounds provided herein are FXR agonists. In another embodiment, the compounds provided herein are FXR antagonists. Agonists that show low efficacy are, in certain embodiments, antagonists. Antagonists include both competitive and non-competitive antagonists. In another embodiment, the compound is an inverse agonist, a partial agonist or a partial antagonist.

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In one embodiment, the compounds for use in the compositions and methods provided herein have the formula (III):

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where n is an integer from 0 to 5; m is an integer from 0 to 4; t is an integer from 0 to 5; each R1a is independently selected from the group consisting of alkyl, hydroxy, alkoxy, alkoxyalkoxy, aralkoxy, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, heteroaryl, heterocyclyl, heterocyclyl (optionally) substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, carboxy, cyano, and alkoxycarbonyl); R2 is hydrogen or alkyl; each R3 is independently selected from the group consisting of alkyl, alkoxy, halo, hydroxy, aralkoxy, alkoxycarbonylalkoxy, aryl (optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, alkoxy, carboxy, alkoxycarbonyl, cyano) , heteroaryl and heterocyclyl; R4 is hydrogen or alkyl; each R5a is independently selected from the group consisting of alkyl, alkoxy, halo, alkylcarbonyl, haloalkoxy, aryl, cyano, carboxy, alkoxycarbonyl, nitro; or two adjacent R5a groups form an aryl, heterocyclyl or heteroaryl; and R6 is hydrogen or alkyl.

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In another embodiment, the compounds for use in the compositions and methods provided herein have the formula (V):

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in which n is an integer from 1 to 5; m is an integer from 0 to 4; t is an integer from 0 to 5; each R1a is selected from the group consisting of alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino; R2 and R6 each is independently hydrogen or alkyl; each R3 is independently selected from the group consisting of alkyl, alkoxy, and halo; and R4 is methyl; each R5a is independently selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, and aryl;

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where each of the above R1-R6 groups, when substituted, are substituted with one or more substituents each independently selected from Q1, where Q1 is halo, pseudohalo, hydroxy, oxo, aunt, nitrile, nitro, formyl, mercapto, carboxy, carboxy alkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl aralkynyl, heteroarilalqui it, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylated minocarbonil or diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralcoxicarboniloxi, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alquilarilaminocarboniloxi, diarilaminocarboniloxi , guanidino, isothioureido, amidino, alkylamidino, arilamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, yl aminoalqu, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, the quilamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino , arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamin or, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + (R24) 3, -P (R25) 2, -P (O) (R25) 2, OP (O) (R25) 2, -N (R24) C ( O) R26, dialquilfosfonilo, alquilarilfosfonilo, diarilfosfonilo, hidroxifosfonilo, alkylthio, arylthio, perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano, alquilsulfiniloxi, alkylsulfonyloxy, arilsulfiniloxi, arylsulfonyloxy, hydroxysulfonyloxy, alcoxisulfoniloxi, aminosulfonyloxy, alquilaminosulfoniloxi, dialquilaminosulfoniloxi, arilaminosulfoniloxi, diarilaminosulfoniloxi, alquilarilaminosulfoniloxi, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylaminosulfonyl; or two Q1 groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy (i.e. -O- (CH2) and O-), thioalkyleneoxy (i.e. -S- (CH2) and O-) or alkylenedithioxy (ie, -S- (CH2) and S-) where y is 1 or 2; or two Q1 groups, which replace the same atoms, together form alkylene;

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each R24 is independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl;

each R25 is independently selected from the group consisting of hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl and -N (R27) R28,

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R26 is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or -N (R27) R28;

R27 and R28 each is independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl,

R27R28

or and together they form alkylene, azalkylene, oxalkylene or tyalkylene;

and each Q1 is optionally substituted with one or more substituents selected from Q2; where each Q2 is independently halo, pseudohalo, hydroxy, oxo, aunt, nitrile, nitro, formyl, mercapto, carboxy, carboxy alkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, containing alkynyl 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl , aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, cycloalkoxy, perfluoroalkoxy, alquenilox i, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralcoxicarboniloxi, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alquilarilaminocarboniloxi, diarilaminocarboniloxi, guanidino, isothioureido, amidino, alkylamidino, arilamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, ariloxicarbonilaminoalquilo, ariloxiarilcarbonilamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, -N + (R24) 3, -P (R25) 2, -P (O) (R25) 2, OP (O) (R25) 2, -N (R24) C (O) R26, dialkylphosphonyl, alkylarylphosphonyl, dia rilfosfonilo, hidroxifosfonilo, alkylthio, arylthio, perfluoroalkylthio, carboxyalkylthio, thiocyano, isothiocyano, alquilsulfiniloxi, alkylsulfonyloxy, arilsurfiniloxi, arylsulfonyloxy, hydroxysulfonyloxy, alcoxisulfoniloxi, aminosulfonyloxy, alquilaminosulfoniloxi, dialquilaminosulfoniloxi, arilaminosulfoniloxi, diarilaminosulfoniloxi, alquilarilaminosulfoniloxi, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q2 groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy (i.e. -O- (CH2) and O-), thioalkyleneoxy (i.e. -S- (CH2) and O-) or alkylenedithioxy (ie, -S- (CH2) and S-) where y is 1 or 2; or two Q2 groups, which replace the same atom, together form alkylene,

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where R24, R25, R26, R27 and R28 are as defined above;

in the form of a stereoisomer, racemate or mixtures thereof; or in the form of a pharmaceutically acceptable derivative thereof.

The groups R1, R2, R3, R4, and R5 are selected such that the resulting compound has nuclear receptor modulating activity, such as in at least one assay described herein, such as FXR antagonist or agonist activity and , in certain embodiments, at an IC50 or EC50 of less than about 100 µM. The ICR or EC50 values of FXR for the compounds provided herein are, in certain embodiments, less than about 50 µM, 25 µM, 10 µM, 1 µM, 100 nM, 10 nM or 1 nM.

Also of interest are any pharmaceutically acceptable derivative, including salts, esters, enol ethers, enol esters, solvates, hydrates and prodrugs of the compounds described herein. Pharmaceutically acceptable salts include amine salts, such as, but not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl -2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts such as, but not limited to, lithium, potassium and sodium; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc, aluminum, and other metal salts such as sodium hydrogen phosphate and disodium phosphate; and also including salts of mineral acids such as hydrochlorides and sulfates; and salts of organic acids, such as acetates, lactates, malate, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates.

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Also provided are pharmaceutical compositions formulated for administration by an appropriate route and medium containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable derivatives thereof, which provides effective amounts for treatment, prevention, or improvement of one or more symptoms of diseases or disorders that are modulator or otherwise affected by the activity of nuclear receptors, including the activity of FXR and / or orphan nuclear receptors, or in which the activity of receptors is involved nuclear, including FXR activity and / or orphan nuclear receptors. The effective amounts and concentrations are effective in improving any of the symptoms of any of the diseases or disorders.

Methods are provided for treatment, prevention,

or improvement of one or more symptoms of diseases or disorders mediated by or in which the activity of nuclear receptors is involved, including the activity of FXR and / or orphan nuclear receptors. Such methods include methods for the treatment, prevention and improvement of one or more symptoms of hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, disease of Parkinson's, cancer, Alzheimer's disease, inflammation, immune disorders, lipid disorders, obesity, conditions characterized by an altered epidermal barrier function, hyperlipidemia, cholestasis; peripheral occlusive disease, ischemic stroke, obesity, pathologies associated with high cholesterol levels, including without limitation, coronary artery disease, pectoral angina, carotid artery disease, strokes, cerebral arteriosclerosis, disorders related to insulin resistance, including without limitation, xanthoma, glucose intolerance, an increase in plasma triglyceride levels and a decrease in high density lipoprotein cholesterol levels, hypertension, hyperuricemia, smaller density lipoprotein particles, and higher levels of inhibitor-1 circulation of plasminogen activator, conditions of altered differentiation or proliferation in excess of the epidermis or mucous membranes, or disorders

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cardiovascular,

using one or plus from  the compounds

provided

 in East  document,  or derivatives

pharmaceutically acceptable thereof.

Methods are also provided to modulate the activity of nuclear receptors, including FXR and / or orphan nuclear receptors, using the compounds and compositions provided herein. The compounds and compositions provided herein are active in assays that measure the activity of nuclear receptors, including FXR and / or orphan nuclear receptors, including the assays provided herein. These methods include positively inhibiting and regulating the activity of nuclear receptors, including FXR and / or orphan nuclear receptors.

Methods for reducing cholesterol levels in a subject as needed by the administration of one or more compounds or compositions provided herein are also provided.

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Methods for modulating cholesterol metabolism are provided using the compounds and compositions provided herein.

Methods are also provided to treat, prevent, or improve one or more symptoms of diseases or disorders that are affected by cholesterol levels, triglycerides,

or bile acids by the administration of one or more of the compounds and compositions provided herein.

In the practice of the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds, which are formulated for systemic delivery, including parenteral, oral, or intravenous delivery, or for local or topical application, are administered for treatment of diseases or disorders mediated by nuclear receptors, including FXR and / or orphan nuclear receptors, or diseases or disorders in which the activity of nuclear receptors is involved, including the activity of FXR and / or orphan nuclear receptors, including hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immune disorders, lipid disorders , obesity, conditions characterized by an altered epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, altered differentiation or proliferation conditions in excess of the epidermis or mucous membranes, or cardiovascular disorders, to an individual showing The symptoms of these diseases or disorders. The amounts are effective in improving or eliminating one or more symptoms of diseases or disorders.

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Manufacturing articles are provided that contain packaging material, a compound or composition, or a pharmaceutically acceptable derivative thereof, provided herein, which is effective for modulating the activity of nuclear receptors, including FXR and / or orphan nuclear receptors, or for the treatment, prevention or improvement of one or more symptoms of diseases or disorders mediated by nuclear receptors, including FXR and / or orphan nuclear receptors, or diseases or disorders in which the activity of nuclear receptors is involved, including the activity of FXR and / or orphan nuclear receptors, within the packaging material, and a label indicating that the compound or composition, or pharmaceutically acceptable derivative thereof, is used to modulate the activity of nuclear receptors, including FXR and / or orphan nuclear receptors,

or for the treatment, prevention or improvement of one or more symptoms of diseases or disorders mediated by nuclear receptors, including FXR and / or orphan nuclear receptors, or diseases or disorders in which the activity of nuclear receptors is involved, including FXR activity and / or orphan nuclear receptors. DETAILED DESCRIPTION OF THE EMBODIMENTS

TO.

Definitions

Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as those usually understood by those skilled in the art to which this invention belongs. In the event that there is a plurality of definitions for a term in this document, those in this section will prevail unless otherwise indicated.

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As used herein, a nuclear receptor is a member of a superfamily of regulatory proteins that are receptors for, for example, steroids, retinoids, vitamin D and thyroid hormones. These proteins bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to a ligand for them. Nuclear receptors can be classified based on DNA binding properties. For example, glucocorticoid, estrogen, androgen, progestin and mineralocorticoid receptors bind in the form of homodimers to hormone response elements (HRE) organized as inverted repeats. Another example is receptors, including those activated by retinoic acid, thyroid hormone, vitamin D3, peroxisome fatty acids / proliferadotes and ecdysone, which bind to HRE in the form of heterodimers with a common partner, the X retinoid receptor (RXR). Among the last receivers are the FXR.

As used herein, an orphan nuclear receptor is a gene product that contains the structural characteristics of a nuclear receptor that was identified without any prior knowledge of its association with a putative ligand and / or for which the natural ligand is unknown. According to this definition, orphan nuclear receptors include, without limitation, the farnesoid X receptor (FXR), liver X receptor (LXR  and ), retinoid X receptor (RXR,  and ), and the receptor activated by the peroxisome proliferator (PPAR , , and ) (see, Giguere (1999) Endocrine Reviews 20 (5): 689-725).

As used herein, the farnesoid X receptor

or FXR refers to all mammalian forms of said receptor including, for example, alternative splicing isoforms and isoforms of natural origin (see, for example, Huber et al. (2002) Gene 290: 35-43). Representative FXR species include, without limitation, rat FXR (GenBank accession number NM_021745), mouse FXR (GenBank accession number NM_009108), and human FXR (GenBank accession number NM_005123).

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As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemicetals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives can easily be prepared by those skilled in this art using known methods for said derivatization. The compounds produced can be administered to animals or humans without substantial toxic effects and are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts such as, but not limited to N, N'dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, Nmethylglucamine, procaine, N-benzylphenethylamine, 1-parachlorobenzyl-2 -pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts, such as lithium, potassium and sodium; alkaline earth metal salts, such as barium, calcium and magnesium; transition metal salts, such as zinc; and other metal salts, such as sodium hydrogen phosphate and disodium phosphate; and also including salts of mineral acids, such as hydrochlorides and sulfates; and salts of organic acids, such as acetates, lactates, malate, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates. Pharmaceutically acceptable esters include alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acid groups, including carboxylic acids, phosphoric acids, phosphonic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include derivatives of formula C = C (OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl

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or heterocyclyl. Pharmaceutically acceptable enol esters include derivatives of formula C = C (OC (O) R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100,

or from 1 to about 10, or from one to about 2, 3 or 4, solvent molecules or water.

As used herein, "treatment" means any way in which one or more of the symptoms of a disease or disorder is improved or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as the use to treat diseases or disorders mediated by nuclear receptors, including FXR and / or orphan nuclear receptors, or diseases or disorders in which the activity of the nuclear receptors, including the activity of FXR and / or orphan nuclear receptors.

As used herein, improvement of the symptoms of a particular disorder by administering a particular pharmaceutical composition or composition refers to a decrease, whether permanent or temporary, lasting or transient that can be attributed to or associated with the administration of the composition.

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As used herein, IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximum response, such as modulation of FXR activity, in an assay that measure that response.

As used herein, EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of the maximum expression of a particular response that is induced, provoked or potentiated by the particular test compound.

As used herein, a prodrug is a compound that, after administration in vivo, is metabolized by one or more stages or processes or otherwise converted into the biological, pharmaceutical or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified so that the active compound is regenerated by metabolic processes. Prodrugs of a compound of the invention can be prepared by modifying functional groups present in the compound of the invention such that the modifications, in routine manipulation or in vivo, are cleaved into the parent compound of the invention. Prodrugs include compounds of the invention in which a hydroxy, amino or mercapto group is attached to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, is cleaved to form a free, amino free hydroxy group or free mercapto, respectively. Examples of prodrugs include acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.

image21

The prodrug can be designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the aroma of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of the pharmacodynamic processes and the metabolism of the drug in vivo, those skilled in this technique can design, once the pharmaceutically active compound is known, prodrugs of the compound (see, for example, Nogrady (1985) Medicinal Chemistry. A Biochemical Approach, Oxford University Press, New York, pages 388-392).

It should be understood that the compounds provided herein may contain chiral centers. Said chiral centers may be of configuration (R) or (S), or it may be a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure, or they may be stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, said residues can be of form L or D. The configuration for amino acid residues of natural origin is generally L. When not specified, the residue is of form L. As used herein, the The term "amino acid" refers to -amino acids that are racemic, or of D or L configuration. The designation "d" preceding the denomination of an amino acid (eg, dAla, dSer, dVal, etc.) refers to the isomer D of the amino acid. The designation "dl" preceding the designation of an amino acid (for example, dIPip) refers to a mixture of the L and D isomers of the amino acid. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Therefore, one skilled in the art will recognize that the administration of a compound in its form (R) is equivalent, for compounds that undergo epimerization in vivo, to the administration of the compound in its form (S). When the compounds described herein contain olefinic double bonds or other centers of geometric symmetry, and unless otherwise specified, the compounds are intended to include both geometric isomers E and Z. Likewise, it is also intended that all forms are included Tautomeric

image22

As used herein, substantially pure means sufficiently homogeneous to appear free of easily detectable impurities determined by conventional methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and spectrometry. mass (MS), used by those skilled in the art to evaluate such purity, or pure enough so that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. The methods of purifying the compounds to produce chemically pure compounds are known to those skilled in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such cases, further purification may increase the specific activity of the compound. Optically active isomers (+) and (-), (R) and (S), or (D) and (L) can be prepared using chiral syntons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. It is used as generally understood by specialists in this technique.

image23

As used herein, the alkyl, alkenyl and alkynyl carbon chains, if not specified, contain 1 to 20 carbons, or 1 to 16 carbons, and are linear or branched. The alkenyl carbon chains of 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds, and the alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds. The alkynyl carbon chains of 2 to 20 carbons, in certain embodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds. Exemplary alkyl, alkenyl and alkynyl groups herein include methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and isohexyl. As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbons to about 6 carbons. As used herein, "alky (in) (in) yl" refers to an alkyl group containing at least one double bond and at least one triple bond.

As used herein, "cycloalkyl" refers to a saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; Cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. The cycloalkenyl and cycloalkynyl groups may contain, in certain embodiments, 3 to 10 carbon atoms, the cycloalkenyl groups containing, in additional embodiments, 4 to 7 carbon atoms and containing the cycloalkynyl groups, in additional embodiments, 8 to 10 carbon atoms The ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of one or two or more rings that can be joined together in a condensed, cross-linked or spiro-connected mode. "Cycloalk (en) (in) yl" refers to a cycloalkyl group containing at least one double bond and at least one triple bond.

image24

As used herein, "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted cycloalkyl", "substituted cycloalkenyl", and "substituted cycloalkynyl" refer to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups and cycloalkynyl, respectively, which are substituted with one or more substituents, in certain embodiments of one to three or four substituents, where the substituents are as defined herein, generally selected from Q1 as defined above in the summary of the invention.

As used herein, "aryl" refers to aromatic monocyclic or multicyclic groups containing 6 to 19 carbon atoms. Aryl groups include groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl and substituted naphthyl.

As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, from about 5 to about 15 members where one or more, in an embodiment of 1 to 3, of the atoms in The ring system is a heteroatom, that is, an element other than carbon, including nitrogen, oxygen or sulfur. The heteroaryl group may optionally be condensed to a benzene ring. Heteroaryl groups include furyl, imidazolyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl.

image25

As used herein, a "heteroaryl" group is a heteroaryl group that is positively charged in one.

or more of the heteroatoms.

As used herein, "heterocyclyl" refers to a monocyclic or multicyclic non-aromatic ring system, in a 3 to 10 member embodiment, in another 4 to 7 member embodiment, in a further 5 to 6 member embodiment. , where one or more, in certain embodiments, from 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including, but not limited to, nitrogen, oxygen or sulfur. In embodiments in which the heteroatom (s) are nitrogen, the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, or nitrogen may be quaternized to form an ammonium group where the substituents are selected as above.

As used herein, "substituted aryl", "substituted heteroaryl" and "substituted heterocyclyl" refer to aryl, heteroaryl and heterocyclyl groups, respectively, which are substituted with one or more substituents, in certain embodiments of one to three or four substituents, where the substituents are as defined herein, generally selected from Q1 as defined above in the summary of the invention.

As used herein, "aralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by an aryl group.

image26

As used herein, "heteroaralkyl" refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, "halo", "halogen" or "halide" refers to F, CI, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups that behave substantially similar to halides. Such compounds can be used in the same way and treated in the same way as halides. Pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, and azide.

As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.

As used herein, "haloalkoxy" refers to -OR in which R is a haloalkyl group.

As used herein, "sulfinyl" or "thionyl" refers to -S (O) -. As used herein, "sulfonyl" or "sulfuryl" refers to -S (O) 2-. As used herein, "sulfo" refers to -S (O) 2O-.

As used herein, "oxycarbonyl" or "carbonyloxy" refers to a divalent radical, -C (O) O-. As used herein, "aminocarbonyl" refers to -C (O) NH2.

As used herein, "alkylaminocarbonyl" refers to -C (O) N (H) R in which R is alkyl, including lower alkyl. As used herein, "dialkylaminocarbonyl" refers to -C (O) N (R ') R in which R' and R are independently alkyl, including lower alkyl; "carboxamide" refers to groups of formula N (R ') C (O) R in which R' and R are independently alkyl, including lower alkyl.

image27

As used herein, "diarylaminocarbonyl" refers to -C (O) N (R) R 'in which R and R' are independently selected from aryl, including lower aryl, such as phenyl.

As used herein, "arylalkylaminocarbonyl" refers to -C (O) N (R) R 'in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R 'is alkyl, including lower alkyl.

As used herein, "arylaminocarbonyl" refers to -C (O) N (H) R in which R is aryl, including lower aryl, such as phenyl.

As used herein, "carboxy" refers to C (O) OH.

As used herein, "alkoxycarbonyl" refers to -C (O) OR in which R is alkyl, including lower alkyl.

As used herein, "aryloxycarbonyl" refers to -C (O) OR in which R is aryl, including lower aryl, such as phenyl.

As used herein, "alkoxy" and "alkylthio" refer to -OR and -SR, wherein R is alkyl, including lower alkyl.

As used herein, "aryloxy" and "arylthio" refer to -OR and -OR, where R is aryl, including lower aryl, such as phenyl.

As used herein, "aralkoxy" refers to OR in which R is aralkyl, such as benzyl.

image28

As used herein, "alkylene" refers to a linear, branched or cyclic divalent aliphatic hydrocarbon group, in certain linear or branched embodiments, which has in one embodiment from 1 to about 20 carbon atoms, which has another realization of 1 to 12 carbons. In a further embodiment, alkylene includes lower alkylene. Optionally, one or more oxygen, sulfur, including S (= O) and S (= O) 2 groups, or optionally substituted nitrogen atoms, including -NR- and N + RR- groups, may be inserted along the alkylene group. the nitrogen substituent (s) are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or COR ', where R' is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OY or -NYY, where Y is hydrogen, alkyl, aryl, heteroaryl , cycloalkyl or heterocyclyl. Alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (- (CH2) 3-), methylenedioxy (-O-CH2-O-) and ethylenedioxy (-O- (CH2) 2-O -). The term "lower alkylene" refers to alkylene groups having 1 to 6 carbons. In certain embodiments, the alkylene groups are lower alkylene, including alkylene of 1 to 3 carbon atoms.

As used herein, "azalkylene" refers to - (CRR) n-NR- (CRR) m-, where n and m are each independently an integer from 0 to 4. As used herein, "oxalkylene "refers to - (CRR) nO- (CRR) m-, where n and m are each independently an integer from 0 to 4. As used herein," tyalkylene "refers to - (CRR) nS- ( CRR) m-, - (CRR) nS (= O) - (CRR) m-, and - (CRR) nS (= O) 2- (CRR) m-, where n and m are each independently an integer of 0 to 4.

As used herein, "alkenylene" refers to a linear, branched or cyclic divalent aliphatic hydrocarbon group, in a linear or branched embodiment, which in certain embodiments has from 2 to about 20 carbon atoms and at least one double link, in other embodiments of 1 to 12 carbons. In other embodiments, the

image29

groups

alkenylene include alkenylene lower.

Optionally

they can insert to the long of the  group

alkenylene

 one or plus  oxygen sulfur  or  atoms

optionally substituted nitrogen, where the nitrogen substituent is alkyl. Alkenylene groups include CH = CH-CH = CH- and -CH = CH-CH2-. The term "lower alkenylene" refers to groups having 2 to 6 carbons. In certain embodiments, the alkenylene groups are lower alkenylene, including alkenylene of 3 to 4 carbon atoms.

As used herein, "alkynylene" refers to a linear, branched or cyclic divalent aliphatic hydrocarbon group, in certain linear or branched embodiments, which has in an embodiment of 2 to about 20 carbon atoms and at least one triple bond, in another embodiment of 1 to 12 carbons. In a further embodiment, alkynylene includes lower alkynylene. Optionally, one or more optionally substituted oxygen, sulfur or nitrogen atoms may be inserted along the alkynylene group, where the nitrogen substituent is alkyl. Aquinylene groups include -CC-CC-, -CC- and -CC-CH2. The term "lower alkynylene" refers to alkynylene groups having 2 to 6 carbons. In certain embodiments, the alkynylene groups are lower alkynylene, including alkynylene of 3 to 4 carbon atoms.

As used herein, "alky (in) (in) ileum" refers to a linear, branched or cyclic divalent aliphatic hydrocarbon group, in certain linear embodiments.

or branched, which has in an embodiment of 2 to about 20 carbon atoms and at least one triple bond, and at least one double bond; in another embodiment of 1 to 12 carbons. In other embodiments, alkyl (in) (in) ileum includes lower alkyl (in) (in) ileum. Optionally, one or more optionally substituted oxygen, sulfur or nitrogen atoms may be inserted along the alkynylene group, where the nitrogen substituent is alkyl. The alkyl (en) (in) ileum groups include -C = C- (CH2) nCC-, where n is 1 or 2, The term "lower alkyl (in) (in) ileum" refers to alkyl groups ( en) (in) ileum that have up to 6 carbons. In certain embodiments, the alkyl (en) (in) ileum groups have approximately 4 carbon atoms.

image30

As used herein, "cycloalkylene" refers to a divalent saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; Cycloalkenylene and cycloalkylene refer to divalent mono- or multicyclic ring systems that include at least one double bond and at least one triple bond respectively. The cycloalkenylene and cycloalkynylene groups may contain, in certain embodiments, 3 to 10 carbon atoms, the cycloalkenylene groups containing certain embodiments of 4 to 7 carbon atoms and the cycloalkylene groups containing certain embodiments of 8 to 10 carbon atoms. The ring systems of the cycloalkylene, cycloalkenylene and cycloalkylene groups may be composed of a ring or two or more rings that may be joined in a condensed, cross-linked or spiro-connected mode. "Cycloalk (en) (in) ileum" refers to a cycloalkylene group containing at least one double bond and at least one triple bond.

image31

As used herein, "substituted alkylene", "substituted alkenylene", "substituted alkynylene", "substituted cycloalkylene", "substituted cycloalkenylene" and "substituted cycloalkenylene" refer to alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene groups and cycloalkylene, respectively, which are substituted with one or more substituents, in certain embodiments of one to three or four substituents, where the substituents are as defined herein, generally selected from Q1 as defined above in the summary of the invention .

As used herein, "arylene" refers to a monocyclic or polycyclic divalent aromatic group, in certain monocyclic embodiments, having in one embodiment from 5 to about 20 carbon atoms and at least one aromatic ring, in another embodiment of 5 to 12 carbons. In other embodiments, arylene includes lower amylene. The arylene groups include 1,2-, 1,3- and 1,4-phenylene. The term "lower arylene" refers to arylene groups having 5 or 6 carbons.

As used herein, "heteroarylene" refers to a divalent monocyclic or multicyclic aromatic ring system, in an embodiment of about 5 to about 15 members where one or more, in certain embodiments of 1 to 3, of the atoms in The ring system is a heteroatom, that is, an element other than carbon, including nitrogen, oxygen or sulfur.

As used herein, "heterocyclylene" refers to a divalent monocyclic or multicyclic non-aromatic ring system, in certain embodiments of 3 to 10 members, in a 4 to 7 member embodiment, in another embodiment of 5 to 6 members , where one or more, including 1 to 3, of the atoms in the ring system is a heteroatom, that is, a non-carbon element, including nitrogen, oxygen or sulfur.

image32

As used herein, "substituted arylene", "substituted heteroarylene" and "substituted heterocyclylene" refer to arylene, heteroarylene and heterocyclylene groups, respectively, which are substituted with one or more substituents, in certain embodiments of one to three or four substituents, where the substituents are as defined herein, generally selected from Q1 as defined above in the summary of the invention.

As used herein, "alkylidene" refers to a divalent group, such as = CR'R, which is attached to an atom of another group, forming a double bond. The alkylidene groups include methylidene (= CH2) and Ethylidene (= CHCH3) As used herein, "arylalkylidene" refers to an alkylidene group in which R 'or R "is an aryl group. The "cycloalkylidene" groups are those in which R 'and R "join together to form a carbocyclic ring. The" heterocyclylidene "groups are those in which at least one of R' and R" contains a heteroatom in the chain, and R 'and R "join to form a heterocyclic ring.

As used herein, "amido" refers to the divalent group -C (O) NH-. "Thioamido" refers to the divalent group -C (S) NH-. "Oxamido" refers to the divalent group -OC (O) NH-. "Thiamido" refers to the divalent group -SC (O) NH-. "Dithiamido" refers to the divalent group -SC (S) NH-. "Ureido" refers to the divalent group -HNC (O) NH-. "Thioureido" refers to the divalent group -HNC (S) NH-.

As used herein, "semicarbazide" refers to -NHC (O) NHNH-. "Carbazate" refers to the divalent group -OC (O) NHNH-. "Isothiocarbazate" refers to the divalent group -SC (O) NHNH-. "Thiocarbazate" refers to the divalent group -OC (S) NHNH-. "Sulfonylhydrazide" refers to the group -SO2NHNH-. "Hydrazide" refers to the divalent group C (O) NHNH-. "Azo" refers to the divalent group -N = N-. "Hydrazinyl" refers to the divalent group -NH-NH-.

image33

When the number of any given substituent is not specified (for example, "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or of different halogens. As another example, "C1-3 alkoxyphenyl" may include one or more of the same or of different alkoxy groups containing one, two or three carbons.

As used in this document, the following terms have their accepted meaning in the chemical literature:

AcOH acetic acid

Cbz benzyl carbamate

CDI carbonyl diimidazole

CHCl3 chloroform

conc. Concentrated

DBU 1,8-diazabicyclo [5.4.0] undec-7-eno

DCM dichloromethane

DME 1,2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethylsulfoxide

EtOAc ethyl acetate

EtOH ethanol (100%)

Et2O diethyl ether

Hex hexanes

H2SO4 sulfuric acid

MeCN acetonitrile

MeOH methanol

Pd (0) palladium (0)

Pd / C palladium on activated carbon PPh3 triphenylphosphine

image34

ASD triethylamine

THF tetrahydrofuran

TFA trifluoroacetic acid

As used herein, the abbreviations for any protective group, amino acid and other compound are, unless otherwise indicated, in accordance with their usual use, recognized abbreviations, or the IUPAC-IUB commission on biochemical nomenclature (see, ( 1972) Biochem. 77: 942944).

B. Quinazolinone modulators of nuclear receptors

Compounds are provided for use in compositions and methods to modulate the activity of nuclear receptors. In particular, compounds are provided for use in compositions and methods for modulating the farnesoid X receptor (FXR) and / or orphan nuclear receptors.

In one embodiment, the compounds are the compounds of formula (III):

image6

in which:

n is an integer from 0 to 5;

m is an integer from 0 to 4;

t is an integer from 0 to 5;

each R1a is independently selected from the group consisting of alkyl, hydroxy, alkoxy, alkoxyalkoxy, aralkoxy, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, heteroaryl, heterocyclyl, heterocyclyl (optionally) replaced with one

image35

or more substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, carboxy, cyano, and alkoxycarbonyl);

R2 is hydrogen or alkyl;

each R3 is independently selected from the group consisting of alkyl, alkoxy, halo, hydroxy, aralkoxy, alkoxycarbonylalkoxy, aryl (optionally substituted with one

or more substituents independently selected from the group consisting of alkyl, halo, alkoxy, carboxy, alkoxycarbonyl, cyano), heteroaryl and heterocyclyl;

R4 is hydrogen or alkyl;

each R5a is independently selected from the group consisting of alkyl, alkoxy, halo, alkylcarbonyl, haloalkyl, haloalkoxy, aryl, cyano, carboxy, alkoxycarbonyl, nitro, and -N (R24) C (O) R26;

or two adjacent R5a groups form an aryl, heterocyclyl or heteroaryl; Y

R6 is hydrogen or alkyl.

Of this group of compounds, a preferred subgroup is those compounds in which m is 0 or 1, n is 1 and each R1a is alkoxy.

Another preferred subgroup is those compounds in which m is 0 or 1, n is 1, 2 or 3 and each R1a is selected from alkyl.

Another preferred subgroup is those compounds in which m is 0 or 1, n is 1 and each R1a is independently selected from halo, haloalkyl, haloalkoxy, and cyano.

image36

Another preferred subgroup is those compounds in which m is 0 or 1, n is 0 or 1 and each R1a is selected from carboxy, dialkylamino, hydroxy, alkoxyalkoxy, alkoxycarbonylalkoxy, aralkoxy, and heterocyclylalkoxy.

Another preferred subgroup is those compounds in which m is 0 or 1, n is 1 and R1a is selected from optionally substituted aryl, heterocyclyl and heteroaryl. Even more preferred in this subgroup are those compounds in which the aryl group is phenyl.

In another embodiment, the compounds for use in the compositions and methods provided herein have the formula (IV):

image6

wherein R1a, R2, R3, R4, R6, R5a, m and n are selected as above; u is an integer from 0 to 4; and R5b is tert-butyl or isopropyl. In another embodiment, R5b is tert-butyl. In another embodiment, R5b is isopropyl.

In another embodiment, the compounds are the compounds of formula (V):

image37

in which:

m is an integer from 0 to 4;

n is an integer from 1 to 5;

t is an integer from 0 to 5;

each R1a is selected from the group consisting of alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino;

R2 and R6 each is independently hydrogen or alkyl;

each R3 is independently selected from the group consisting of alkyl, alkoxy, and halo; Y

R4 is methyl;

each R5a is independently selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, halo, and aryl

or two adjacent R5a groups form an aryl, heterocyclyl or heteroaryl.

Of this group of compounds, a preferred subgroup is those compounds in which m is 0 or 1, n is 1 and each R1a is alkoxy.

Another preferred subgroup is those compounds in which m is 0 or 1, n is 1, 2 or 3 and each R1a is selected from alkyl.

Another preferred subgroup is those compounds in which m is 0 or 1, n is 0 or 1 and each R1a is independently selected from dialkylamino, aralkoxy, halo, haloalkyl and haloalkoxy.

In another embodiment, the compounds for use in the compositions and methods provided herein have any of formulas III to V, wherein Q2 is halo, pseudohalo, aralkoxy or nitro; or any two Q2 groups, which replace adjacent carbons, together form alkylenedioxy. In another embodiment, Q2 is nitro, fluoro, benzyloxy or chloro; or two Q2 groups, which replace adjacent carbons, together form methylenedioxy.

image38

Of the compounds described herein, the most preferred compounds are those selected from the group consisting of the following: 4-tert-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3 , 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-tert-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; and biphenyl-4-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide.

C. Preparation of the compounds

The starting materials in the synthesis examples provided in this document are available from commercial sources or through literature procedures. All commercially available compounds were used without further purification unless otherwise indicated. CDCl3 (99.8% D, Cambridge Isotope Laboratories) was used in all the indicated experiments. Resonance spectra

image39

Proton nuclear magnetic (NMR) (1H) were recorded on a Bruker Avance 400 MHz NMR spectrometer. Significant peaks are tabulated and typically include: the number of protons, and the multiplicity (s, singlet; d, 5 doublet; t , triplet; q, quartet; m, multiplet; sa, wide singlet). Chemical shifts are presented as parts per million () relative to tetramethylsilane. Low resolution (MS) mass spectra were obtained as electrospray ionization mass spectra 10 (ESI), which were recorded on a Perkin-Elmer SCIEX HPLC / MS instrument using reverse phase conditions (acetonitrile / water, acid 0.05% trifluoroacetic acid). Flash chromatography was performed using Merck silica gel 60 (230-400 mesh) following the conventional protocol

15 (Still et al. (1978) J. Org. Chem. 43, 2923). Substituted methyl anthranilates are commercially available or can be obtained synthetically from commercially available starting materials, using conventional literature protocols (Scheme 1) in

20 which R is typically a halogen, alkyl, or alkoxy. SCHEME 1

image6

N-acyl methyl anthranilates 3 are prepared by treating methyl anthranilate 1 with an acid chloride 2 in which R1 is typically alkyl, aryl, or heteroaryl (Scheme 2).

image40

SCHEME 2

image41

10

Acid chlorides are commercially available and / or can be prepared using conventional methods found in the literature. R1 is typically 1-chloroethyl or a product derived from protected amino acids, for example, N

15 CBZ glycine. In case protected amino acids are used, alternative acylation conditions are required (Yu, Melvin, et al. (1992) J. Med. Chem. 35: 2534-2542). For example, protected amino acid 4 is treated with carbonyl diimidazole (CDI) followed by subsequent treatment of a

20 substituted methyl anthranilate 1 to produce the N-acyl methyl anthranilate 3 (Scheme 3). Again, chemical diversity continues to vary R and R1 as previously described.

SCHEME 3

25

image6

image42

The quinazolinone 5 core was prepared by acylating an amine with N-acyl anthranilic acid followed by tandem cyclodehydration by thermolysis (Rao et al. (1985) J. Indian Chem.:234-237). N-acyl anthranilic acid

5 3 was treated with phosphorus trichloride and an amine, under reflux conditions, to produce the desired quinazolinones 5 (Scheme 4) in which R2 typically includes an aryl (aniline), heteroaryl, or primary amines. When 3 has a protected amino extension, conditions are required

10 alternatives to generate the core (6) (Yu et al. (1992) J. Med. Chem. 35: 2534-2542). SCHEME 4

image43

For example, compound 3 was treated with carbonyl diimidazole in which the resulting activated acid was treated with an amine (R2-NH2) under reflux conditions to produce quinazolinone 6 (Scheme 5).

image44

SCHEME 5

image6

The protected amino extension was then deprotected using conventional conditions found in references in the literature (Greene et al. Protective Groups in Organic Synthesis, 3rd Ed. (John Wiley, NY (1999))). For example, compound 5 was subjected to hydrogenation conditions to produce a free amine 7 (Scheme 6). Subsequently, the free amine was treated with several electrophiles (R3) to produce a diverse series of quinazolinone analogues (8) in which R3 is typically an amide or sulfonamide but without limitation to these groups. Additional electrophiles include carboxylic acids and derivatives thereof, sulfonyl chlorides, isocyanates, alkyl halides, aldehydes, ketones, and chloroformates.

image6

image45

SCHEME 6

image6

Alternatively, when R1 is a substituted 1-chloroalkyl (9), various nucleophiles are introduced, ie, 5 amines, alcohols, cuprates etc. For example, when 1'-chloro ethyl quinazolinone 9 was treated with an amine under the appropriate conditions, quinazolinone 10 (Scheme 7A) was achieved. Subsequently, when R4 is equal to hydrogen, 10 was treated with various electrophiles to produce

10 compounds such as 11, wherein R4 is typically an amide or sulfonamide, although without limitation (Scheme 7B). Additional electrophiles include carboxylic acids and derivatives thereof, sulfonyl chlorides, isocyanates, alkyl halides, aldehydes, ketones, and chloroformates.

15 5

image46

image6

10

SCHEME 7A

fifteen

image6

image47

SCHEME 7B

image6

A quinazolinone containing aryl bromide (12)

5 can be further manipulated with the addition of various structural modifiers using conventional C-C, C-N, and C-O bond formation reactions. The purpose of this was to gain access to a variety of analogues that were accessible through the methods described

10 previously. For example, a bromo-substituted heterocycle can be manipulated using conventional transition metal chemistry to introduce a wide range of diverse functionalities that are otherwise difficult to obtain using alternative methods (Hegedus, Louis, S. Transition Metals in

15 the Synthesis of Complex Organic Molecules, University Science Books: Mill Valley, CA (1994)). Quinazolinone 12 was treated with Pd (0) and a phosphorus ligand in the presence of the appropriate coupling partner (R5) to produce a new series of quinazolinone analogs similar to 13 (Scheme 8). A typical reagent (R5) would include boronic acids, (esters), amines, amides, mono-substituted alkynes, alcohols, or organotin reagents. These

image48

5 reagents are typically aryl, heteroaromatic, and alkyl in nature. In addition, these monomer reagents are commercially available and / or can be synthesized using known methodologies from the literature.

10

SCHEME 8

image6

Similarly, compound 14 was modified using the

15 same chemistry described above. The conditions and reagents used to modify the N-aryl quinazolinones 14 are identical to those previously described. Compound 14 was treated with Pd (0) and a phosphorus ligand in the presence of an appropriate monomer (R5) to produce N-aryl quinazolinones.

20 substituted as the as 15 (Scheme 9). A typical monomer (R5) would include boronic acids, amines, amides, mono-substituted alkynes, alcohols, or organotin reagents. These monomers are typically aryl, heteroaromatic, and alkyl in nature. In addition, these reagents

image49

monomeric

 is it so available in he  market and / or can

synthesize

using methodologies  known  from the

bibliography.

SCHEME 9

5

image6

15 Additional modifications were made to the quinazolinone core by demethylating the quinazolinone 16 methoxyphenyl ether to expose a phenol 17 as a starting point for diversity. Methoxy phenyl ethers are typically demethylated using a variety of methods of

20 the bibliography (McOmie, J. F. W., West, D.E. Org. Synth., Collect. Vol. V, 412 (1973): Jung, M. E., Lyster, M. A., J. Org. Chem., 42, 3761 (1977)). For example, when 16 is treated with boron tribromide, the exclusive formation of phenol 17 is observed (Scheme 10). Similarly, the N-aril

Quinozolinone substituted methoxy 18 was manipulated using the same protocol outlined above to produce compound 19 (Scheme 11). SCHEME 10

image50

SCHEME 11

image6

5

The treatment of a phenol with a diversity of electrophiles establishes another path to introduce diversity, which is not easily accessible with other methodologies. For example, phenol 17 was treated with various

10 electrophiles, that is, alkyl halides, isocyanates and acid chlorides to produce ethers, carbamates and esters, respectively. In addition, phenol 17 was converted into various ethers 20 using the Mitsunobu reaction (Mitsunobu, O .; Yamada, M. Bull. Chem. Soc. Jpn., 1967, 40,2380; Canp, D .;

15 Jenkins, I.D. Aust J. Chem., 1988, 41, 1835). Compound 17 was treated with triphenylphosphine, alcohol (R5OH) and diisopropyl azodicarboxylate (DIAD) to produce quinazolinone 20 (Scheme 12). Typical alcohols that were used include primary and secondary aliphatic alcohols. But nevertheless,

20 alcohols containing other functionalities were also used, for example, ethyl glycolate.

image51

SCHEME 12

image52

Similarly, compound 19 could be converted from

In a manner identical to that described above to achieve similar analogs to 21. A large series of diverse functionalities can be introduced which are otherwise difficult to obtain using alternative methods (Scheme 13).

20 SCHEME 13 D. Formulation of pharmaceutical compositions

image6

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The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the nuclear receptor activity modulators provided herein that are useful in the prevention, treatment, or improvement of one or more of the disease symptoms. or disorders associated with the activity of nuclear receptors, including the activity of FXR and / or orphan nuclear receptors. Such diseases or disorders include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease , inflammation, immune disorders, lipid disorders, obesity, conditions characterized by an altered function of the epidermal barrier, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of altered differentiation or excessive proliferation of the epidermis or membranes mucous membranes and cardiovascular disorders.

The compositions contain one or more compounds provided herein. The compounds are preferably formulated in suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as preparations of transdermal patches and dry powder inhalers. Typically, the compounds described above are formulated in pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).

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In the compositions, effective concentrations of one or more pharmaceutically acceptable compounds or derivatives are mixed with a suitable pharmaceutical medium or vehicle. The compounds may be derivatized in the form of the corresponding salts, esters, enol ethers or esters, acids, bases, solvates, hydrates or prodrugs before formulation, as described above. The concentrations of the compounds in the compositions are effective for the delivery of an amount, after administration, that treats, prevents, or improves one or more of the symptoms of diseases or disorders associated with the activity of nuclear receptors or in which is involved in the activity of nuclear receptors. Such diseases or disorders include, but are not limited to, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease , inflammation, immune disorders, lipid disorders, obesity, conditions characterized by an altered function of the epidermal barrier, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of altered differentiation or excessive proliferation of the epidermis or membranes mucous membranes and cardiovascular disorders.

Typically, the compositions are formulated for administration of a single dosage. To formulate a composition, the heavy fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selective vehicle at an effective concentration so as to alleviate or improve the condition treated. Pharmaceutical media or vehicles suitable for the administration of the compounds provided herein include any vehicle known to those skilled in the art suitable for the particular mode of administration.

image55

In addition, the compounds may be formulated as a pharmaceutically active ingredient exclusive in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-directed liposomes, such as tumor-directed liposomes, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in US Patent No. 4,522,811. In summary, liposomes such as multilamellar vesicles (MLV) can be formed by spraying ovum phosphatidylcholine and cerebral phosphatidylserine (7: 3 molar ratio) inside a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove the non-encapsulated compound, sedimented by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects in the treated patient. The therapeutically effective concentration can be determined empirically by testing the compounds in in vitro and in vivo systems described herein and in international patent application publications No. 99/27365 and 00/25134 (see, for example, EXAMPLES 15 and 16) and then extrapolated from them for dosages for humans.

image56

The concentration of active compound in the pharmaceutical composition will depend on the rates of absorption, inactivation and excretion of the active compound, the physicochemical characteristics of the compound, the dosing schedule, and the amount administered as well as other factors known to those skilled in the art. For example, the amount supplied is sufficient to improve one or more of the symptoms of diseases or disorders associated with the activity of nuclear receptors or in which the activity of nuclear receptors is involved, as described herein. .

Typically, a therapeutically effective dosage should produce a serum concentration of active ingredient of about 0.1 ng / ml to about 50-100 µg / ml. Pharmaceutical compositions should typically provide a dosage of about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical unit dosage forms are prepared to provide from about 1 mg to about 1000 mg and preferably from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per unit dosage form.

The active ingredient can be administered at once, or it can be divided into several smaller doses to be administered at time intervals. It is understood that precise dosing and duration of treatment is a function of the disease being treated and can be determined empirically using known test protocols or by extrapolation of test data in vivo or in vitro. It should be appreciated that concentrations and dosage values may also vary with the severity of the condition to be relieved. Additionally, it should be understood that for any particular subject, the specific dosage regimens must be adjusted over time according to the individual need and professional judgment of the person who is administering or supervising the administration of the compositions, and that the concentration ranges exposed in this document they are only exemplary and are not intended to limit the scope or practice of the claimed compositions.

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Pharmaceutically acceptable derivatives include acids, bases, enol ethers and esters, salts, esters, hydrates, solvates and prodrug forms. The derivative is selected so that its pharmacokinetic properties are superior to the corresponding neutral compound.

Thus, the concentrations or effective amounts of one or more of the compounds described herein or pharmaceutically acceptable derivatives thereof are mixed with a pharmaceutical medium or vehicle suitable for systemic, topical or local administration to form pharmaceutical compositions. The compounds are included in an amount effective to improve one or more symptoms of, or to treat or prevent diseases or disorders associated with the activity of nuclear receptors or in which the activity of nuclear receptors is involved, as described herein. document. The concentration of the active compound in the composition will depend on the rates of absorption, inactivation, excretion of the active compound, the dosage schedule, the amount administered, the particular formulation as well as other factors known to those skilled in the art.

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The compositions are intended to be administered by a suitable route, including oral, parenteral, rectal, topical and local. For oral administration, capsules and tablets are currently preferred. The compositions are in liquid, semi-solid or solid form and are formulated in a manner suitable for each route of administration. Preferred modes of administration include parenteral and oral modes of administration. Oral administration is currently the most preferred.

The solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application may include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methylparabenos; antioxidants, such as ascorbic acid and sodium disulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations may be included in ampoules, disposable syringes or single-dose or multi-dose vials made of glass, plastic or other suitable material.

In cases where the compounds show insufficient dimethylsulfoxide (DMSO), the use of surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds, can be used in the formulation of effective pharmaceutical compositions.

solubility,

they can be used methods for solubilize the

compounds.

 Sayings  methods They are  acquaintances  for the

specialists

in the technique and include, though without

limitation,

 he use from co-solvents, such  how

image59

After mixing or adding the compound or compounds, the resulting mixture may be a solution, suspension, emulsion or the like. The shape of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected medium or vehicle. The effective concentration is sufficient to improve the symptoms of the disease, disorder or condition treated and can be determined empirically.

The pharmaceutical compositions are provided for administration to humans and animals in unit dosage form, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-in-water emulsions that they contain adequate amounts of the pharmaceutically acceptable compounds or derivatives thereof. Therapeutically active pharmaceutical compounds and derivatives thereof are typically formulated and administered in unit dosage forms or multiple dosage forms. The single-dose forms as used herein refer to physically discrete units suitable for human and animal subjects and individually packaged as is known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical medium, vehicle or diluent. Examples of single dose forms include ampoules and syringes and individually packaged tablets or capsules. The single-dose forms can be administered in fractions or multiples thereof. A multidose form is a plurality of identical single-dose forms packaged in a single container to be administered in segregated single-dose form. Examples of multi-dose forms include vials, tablet bottles or capsules or pints or gallon bottles. Therefore, the multidose form is a multiple of single doses that are not segregated in the package.

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The composition may contain together with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethyl cellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum arabic, gelatin, glucose, molasses, polyvinyl pyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those skilled in the art. Liquid compositions that can be administered pharmaceutically can be prepared, for example, by dissolving, dispersing, or otherwise mixing a previously defined active compound and optional pharmaceutical adjuvants in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other of these agents. Actual methods for preparing such dosage forms are known, or will be apparent to those special in this technique; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975. The composition or formulation to be administered will contain, in any case, an amount of the active compound in an amount sufficient to relieve the symptoms of treated subject.

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Dosage forms or compositions containing the active ingredient in the range of 0.005% to 100% may be prepared, the balance being composed of a non-toxic vehicle. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium , glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained-release formulations such as implants and microencapsulated delivery systems, and biodegradable and biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. . The methods for preparing these compositions are known to those skilled in the art. The compositions contemplated may contain 0.001% -100% active ingredient, preferably 0.1-85%, typically 75-95%.

The active compounds or pharmaceutically acceptable derivatives can be prepared with vehicles that protect the compound against rapid removal from the body, such as time-release formulations or coatings. The compositions may include other active compounds to obtain combinations of desired properties. The compounds provided herein, or pharmaceutically acceptable derivatives thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent that is known in the general art that is valuable in the treatment of a or more of the diseases or medical conditions mentioned above in this document, such as diseases or disorders associated with the activity of nuclear receptors or in which the activity of nuclear receptors is involved. It should be understood that such combination therapy constitutes an additional aspect of the compositions and methods of treatment provided herein.

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1. Compositions for oral administration

The oral dosage dosage forms are solid, gel or liquid. Solid dosage forms are tablets, capsules, granules and coarse powders. Types of oral tablets include compressed, chewable and compressed dragees that may have an enteric coating, a sugar coating or a film coating. The capsules may be hard or soft gelatin capsules, while the granules and powders may be provided in a non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, preferably capsules or tablets. Tablets, pills, capsules and troches may contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; an emollient; a sweetening agent; and a flavoring agent.

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Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, gum arabic mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopene and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Emollients include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methyl cellulose, agar and carboxymethyl cellulose. Coloring agents include, for example, any of the certified and approved water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended in alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any of several spray-dried flavors. Flavoring agents include natural aromas extracted from plants such as fruits and synthetic mixtures of compounds that produce a pleasant sensation, such as, but not limited to, mint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoexitylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammonia shellac and cellulose acetate phthalates. Film coatings include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other similar ingredient.

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When the unit dosage form is a capsule, it may contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, the unit dosage forms may contain several different materials that modify the physical form of the dosage unit, for example, sugar coatings and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, hyssop, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorants and aromas.

The active materials can also be mixed with other active materials that do not alter the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers and diuretics. The active ingredient is a pharmaceutically acceptable compound or derivative thereof as described herein. Higher concentrations of up to about 98% by weight of the active ingredient may be included.

The pharmaceutically acceptable carriers included in the tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar-coated tablets are tablets that are compressed to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets are tablets that have been coated with a polymer or other suitable coating. Multiple tablets that are compressed are tablets that are tablets manufactured for more than one compression cycle using the pharmaceutically acceptable substances mentioned above. Coloring agents can also be used in the above dosage forms. Flavoring and sweetening agents are used in tablets that are compressed, sugar coated, multiple compression and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and dragees.

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Liquid oral dosage forms include solutions, emulsions, aqueous suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. The emulsions are oil in water or water in oil.

Elixirs are sweetened and transparent hydroalcoholic preparations. Pharmaceutically acceptable vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which a liquid in the form of small blood cells is dispersed in another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted in a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted in a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

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Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cotton oil. Examples of emulsifying agents include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspension agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum and gum arabic. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the certified and approved water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural aromas extracted from plants such as fruits, and synthetic mixtures of compounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension in, for example, propylene carbonate, vegetable agents or triglycerides, is preferably encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are described in US Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, for example, in a polyethylene glycol, can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example, water, to be easily measured for administration.

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Alternatively, liquid or semi-solid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, polyethylene glycol esters (e.g., propylene carbonate) and other of these vehicles, and encapsulating these solutions or suspensions in hard or soft gelatin capsule covers. Other useful formulations include those set forth in U.S. Patents No. Re 28,819 and

4,358,603. In summary, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or polyalkylene glycol including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750 dimethyl ether where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include aqueous alcoholic solutions that include a pharmaceutically acceptable acetal. The alcohols used in these formulations are any pharmaceutically acceptable water miscible solvent having one or more hydroxyl groups, including propylene glycol and ethanol. Acetals include di (lower alkyl) acetals of lower alkyl aldehydes such as diethyl acetal acetaldehyde.

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In all embodiments, tablet and capsule formulations may be coated as those skilled in the art know to modify or sustain the solution of the active ingredient. Thus, for example, they can be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectable solutions and emulsions

This document also contemplates parenteral administration, generally characterized by injection, subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as, by example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. This document also contemplates the implantation of a slow-release or sustained-release system, so that a constant level of dosage is maintained (see, for example, US Patent No. 3,710,795). In summary, a compound provided herein is dispersed in a solid internal matrix, for example, polymethylmethacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene interphthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, copolymer ethylene-vinyl acetate, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate, which is surrounded by a polymeric membrane external, for example, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers ilo with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol copolymer, and ethylene / Vinylxethanol, which is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a stage that controls the rate of release. The percentage of active compound contained in said parenteral compositions depends greatly on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

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Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile powder-soluble products, such as lyophilized powders, ready to be combined with a solvent just before use, including hypodermic tablets, sterile suspensions ready for injection, powder-insoluble products Sterile ready to be combined with a vehicle just before use and sterile emulsions. The solutions may be aqueous or non-aqueous.

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If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include sodium chloride injection, Ringer injection, isotonic dextrose injection, sterile water injection, dextrose injection and Ringer's lactate. Non-aqueous parenteral vehicles include fixed oils of plant origin, cotton oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations should be added to parenteral preparations packaged in multidose containers that include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl esters p-hydroxybenzoic, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspension agents and dispersants include sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Emulsifying agents include polysorbate 80 (TWEEN® 80). A metal ion sequestering or chelating agent includes EDTA. Pharmaceutical vehicles also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid and lactic acid for pH adjustment.

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The concentration of the pharmaceutically active compound is adjusted so that an injection provides an amount effective to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.

Parenteral single dose preparations are packaged in a vial, vial or syringe with a needle. All preparations for parenteral administration should be sterile, as you know and practice in the art.

Illustratively, an intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an injected active material as necessary to produce the desired pharmacological effect.

Injectables are designed for local and systemic administration. Typically, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w / w to about 90% w / w or more, preferably more than 1% w / w of the active compound for the tissue or treated tissues. The active ingredient can be administered at once, or it can be divided into several smaller doses to be administered at time intervals. It is understood that precise dosing and duration of treatment is a function of the tissue being treated and can be determined empirically using known test protocols or by extrapolation from live or in vitro test data. It should be appreciated that concentrations and dosage values may also vary with the age of the treated individual. It should be further understood that for any particular subject, the specific dosage regimens should be adjusted over time according to the need of the individual and the professional judgment of the person who is administering or supervising the administration of the formulations, and that the concentration intervals set forth herein are only exemplary and are not intended to limit the scope or practice of the claimed formulations.

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The compound may be suspended in micronized form or another suitable form or it may be derivatized to produce a more soluble active product or to produce a prodrug. The shape of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected medium or vehicle. The effective concentration is sufficient to

improve the symptoms of the condition or empirically. 3. Freeze dried powders

can be determined

In this document too

are from interest the powder

lyophilisates, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.

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The sterile lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient that improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that can be used include dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or another of these buffers known to those skilled in the art, typically at approximately neutral pH. Subsequent sterility filtration of the solution followed by lyophilization under conventional conditions known to those skilled in the art provides the desired formulation. Generally, the resulting solution is distributed in vials for lyophilization. Each vial will contain a single dosage (10-1000 mg, preferably 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as about 4 ° C at room temperature.

Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, preferably 5-35 mg, more preferably about 9-30 mg of lyophilized powder, per ml of sterile water or other suitable vehicle are added. The precise amount depends on the selected compound. Said amount can be determined empirically.

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4. Topical administration

Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like and is formulated in the form of creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, dyes, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages , dermal patches or any other formulation suitable for topical administration.

The pharmaceutically acceptable compounds or derivatives thereof can be formulated in the form of aerosols for topical application, such as by inhalation (see, for example, United States Patents No. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for the supply of a steroid useful for the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract may be in the form of an aerosol or solution for a nebulizer, or in the form of a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In that case, the formulation particles will typically have diameters of less than 50 micrometers, preferably less than 10 micrometers.

The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intramedullary application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound may also be administered alone or in combination with other pharmaceutically acceptable excipients.

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These solutions, particularly those intended for ophthalmic use, can be formulated as 0.01% -10% isotonic solutions, pH approximately 5-7, with appropriate salts.

5. Compositions for other routes of administration

This document also contemplates other routes of administration, such as topical application, transdermal patches, and rectal administration.

For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories as used herein mean solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases can be used. Agents for raising the melting point of suppositories include whale sperm and wax. Rectal suppositories can be prepared by compression method or by molding. The typical weight of a rectal suppository is approximately 2 to 3 g.

Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for oral administration formulations.

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6. Manufacturing items

Pharmaceutically acceptable compounds or derivatives may be packaged in the form of articles of manufacture containing packaging material, a pharmaceutically acceptable compound or derivative thereof provided herein, which is effective in modulating the activity of nuclear receptors, including FXR and / or orphan nuclear receptors, or for the treatment, prevention or improvement of one

or more symptoms of diseases or disorders mediated by nuclear receptors, including FXR and / or orphan nuclear receptors, or diseases or disorders in which the activity of nuclear receptors is involved, including the activity of FXR and / or orphan nuclear receptors , within the packaging material, and a label indicating that the compound or composition, or pharmaceutically acceptable derivative thereof, is used to modulate the activity of nuclear receptors, including FXR and / or orphan nuclear receptors, or for treatment, prevention or improvement of one or more symptoms of diseases or disorders mediated by nuclear receptors, including FXR and / or orphan nuclear receptors, or of diseases or disorders in which the activity of nuclear receptors is involved, including the activity of FXR and / or from orphan nuclear receptors.

The manufacturing items provided in this document contain packaging materials. Packaging materials for use in pharmaceutical packaging products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide range of formulations of the compounds and compositions provided herein are contemplated as there is a variety of treatments for any disease or disorder in which the activity of nuclear receptors is involved, including the activity of FXR and / or Orphan nuclear receptors, as a mediator or contributor to the symptoms or cause.

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E. Evaluation of compound activity

Conventional physiological, pharmacological and biochemical procedures are available to test compounds to identify those that have biological activities that modulate the activity of nuclear receptors, including FXR and / or orphan nuclear receptors. Such assays include, for example, biochemical assays such as binding assays, fluorescence polarization assays, recruitment assays of FRET-based co-activators (see, in general, Glickman et al., J. Biomolecular Screening (2002 ), Vol. 7, No. 1, page 3-10), as well as cell-based assays including the co-transfection assay, the use of LBD-Gal 4 chimeras and protein-protein interaction assays (see, Lehmann. et al., J. Biol Chem. (1997), Vol. 272, No. 6, p. 3137-3140).

High performance scanning systems are commercially available (see, for example, Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments Inc., Fullerton, CA; Precision Systems, Inc., Natick, MA) that enable these tests to be performed in a high performance mode. These systems typically automate complete procedures, including all pipetting of samples and reagents, liquid dosing, timed incubations, and final microplate readings at the appropriate detector (s) for the assay. These configurable systems provide high performance and rapid startup as well as a high degree of flexibility and adequacy. The manufacturers of such systems provide detailed protocols for various high performance systems. Thus, for example, Zymark Corp. provides technical bulletins that describe scanning systems to detect modulation of gene transcription, ligand binding, and the like.

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Assays that do not require washing or liquid separation steps are preferred for such high performance scanning systems and include biochemical tests such as fluorescence polarization assays (see, for example, Owicki, J., Biomol. Screen (2000 ), October, Vol. 5, No. 5, p. 297), scintillation proximity tests (SPA) (see, for example, Carpenter et al., Methods Mol. Biol. (2002), Vol. 190, p. 31-49) and fluorescence resonance energy transfer (FRET) or recruitment assays of time-based FRET-based co-activators (Mukherjee et al., J. Steroid Biochem. Mol. Biol. (2002); Vol 81, No. 3, p. 217-25; Zhou et al., Mol. Endocrinol. (1998), Vol. 12, No. 10, p. 1594-604). Generally such assays can be performed using the full length receptor, or isolated ligand binding domain (LBD). In the case of FXR the LBD comprises amino acids 244 to 472 of the full length sequence.

If a fluorescently labeled ligand is available, fluorescence polarization assays provide a way to detect the binding of compounds to the nuclear receptor of interest by measuring changes in fluorescence polarization that occurs as a result of the displacement of a trace amount. of the ligand marker by the compound. In addition, this approach can also be used to control the ligand-dependent association of a fluorescently labeled co-activating peptide with the nuclear receptor of interest to detect ligand binding to the nuclear receptor of interest.

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The ability of a compound to bind to a receptor, or a heterodimeric complex with RXR, can also be measured in a homogeneous assay format by evaluating the extent to which the compound can compete with a radiolabeled ligand with affinity known to the receptor using an assay of scintillation proximity (SPA). In this approach, the radioactivity emitted by a radiolabeled compound generates an optical signal when it is placed in close proximity to a scintillation agent such as a pearl containing YSI copper, to which the nuclear receptor is attached. If the radiolabeled compound is displaced from the nuclear receptor, the amount of light emitted from the scintillation agent attached to the nuclear receptor decreases, and this can be easily detected using liquid scintillation plate readers in conventional microplates such as, for example, a Wallac reader MicroBeta

Heterodimerization of FXR with RXR can also be measured by fluorescence resonance energy transfer (FRET), or time-resolved FRET, to control the ability of the compounds provided herein to bind FXR or other nuclear receptors. Both approaches depend on the fact that the transfer of energy from a donor molecule to a recipient molecule only occurs when the donor and the acceptor are in close proximity. Typically, the purified LBD of the nuclear receptor of interest is labeled with biotin, then mixed with stoichiometric amounts of streptavidin labeled with Europium (Wallac Inc.), and the purified LBD of RXR is labeled with a suitable fluorophore such as CY5 ™. Equimolar amounts of each modified LBD are mixed together and allowed to equilibrate for at least 1 hour before the addition of variable or constant concentrations of the sample for which affinity has to be determined. After equilibration, the time-resolved fluorescent signal is quantified using a fluorescent plate reader. The affinity of the compound can then be estimated from a representation of the fluorescence against the concentration of compound added.

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This approach can also be exploited to measure the ligand-dependent interaction of a co-activating peptide with a nuclear receptor to characterize the agonist or antagonistic activity of the compounds described herein. Typically, the assay in this case involves the use of a recombinant glutathione-Stransferase (GST) fusion ligand-binding domain (LBD) of the nuclear receptor and a sequenced synthetic biotinylated peptide derived from the interaction domain with the receptor. a co-activator peptide such as the steroid receptor co-activator 1 (SRC-1). Typically GST-LBD is labeled with a europium chelate (donor) by an anti-GST antibody labeled with europium, and the co-activating peptide is labeled with allophycocyanin by a streptavidin-biotin bond.

In the presence of an agonist for the nuclear receptor, the peptide is recruited to the GST-LBD by placing europium and allophycocyanin in close proximity to enable the transfer of energy from the europium chelate to the allophycocyanin. After excitation of the complex with light at 340 nm, the excitation energy absorbed by the chelate of europium is transmitted to the rest of allophycocyanin causing emission at 665 nm. If the europium chelate is not placed in close proximity to the rest of allophycocyanin, there is little or no energy transfer and the excitation of the europium chelate causes emission at 615 nm. Therefore, the intensity of the light emitted at 665 nm gives an indication of the strength of the protein-protein interaction. The activity of a nuclear receptor antagonist can be measured by determining the ability of a compound to competitively inhibit (i.e., IC50) the activity of an agonist for the nuclear receptor.

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In addition, a variety of cell-based assay methodologies can be used successfully in screening assays to identify and form a profile of the specificity of the compounds of the present invention. These approaches include the co-transfection assay, translocation assays, complementation assays and the use of gene activation technologies to overexpress endogenous nuclear receptors.

There are three basic variants of the co-transfection assay strategy, co-transfection assays using a full length nuclear receptor, co-transfection assays using chimeric nuclear receptors comprising the ligand binding domain of the nuclear receptor of interest fused to a heterologous DNA binding domain, and assays based on the use of the mammalian double hybrid assay system.

The basic co-transfection assay is based on the cotransfection in the cell of an expression plasmid to express the nuclear receptor of interest in the cell with an reporter plasmid comprising an reporter gene whose expression is under the control of a sequence of DNA that is capable of interacting with that nuclear receptor (see, for example, U.S. Patent Nos. 5,071,773; 5,298,429, 6,416,957, WO 00/76523). Treatment of transfected cells with an agonist for the nuclear receptor increases the transcriptional activity of that receptor that is reflected by an increase in the expression of the reporter gene, which can be measured by a variety of conventional procedures.

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For those receptors that function as heterodimers with RXR, such as FXRs, the cotransfection assay typically includes the use of expression plasmids for both the nuclear receptor of interest and for RXR. Typical co-transfection assays require access to the full-length nuclear receptor and appropriate response elements that provide sufficient sensitivity and specificity of exploration for the nuclear receptor of interest.

Genes encoding the following previously described full-length proteins, which are suitable for use in co-transfection studies and profiling of the compounds described herein, include rat FXR (GenBank Accession No. NM_021745 ), Human FXR (GenBank Accession No. NM_005123), Human RXR (GenBank Accession No. NM_002957), Human RXR (GenBank Accession Number XM_042579), Human RXR (GenBank Accession Number XM_053680), LXR  human (GenBank accession number NM_005693), human LXR (GenBank accession number NM_007121), human PPAR (GenBank accession number NM_005036) and human PPAR (GenBank accession number NM_006238).

Reporter plasmids can be constructed using conventional molecular biology techniques by placing cDNA encoding the reporter gene downstream of a suitable minimum promoter. For example, luciferase reporter plasmids can be constructed by placing cDNA encoding firefly luciferase immediately downstream of the herpes virus thymidine kinase promoter (located at nucleotide residues -105 to +51 of the thymidine kinase nucleotide sequence) which is in turn linked to the appropriate response element (RE).

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Those skilled in the art know numerous methods for co-transfecting expression plasmids and reporters and can be used for the cotransfection assay to introduce plasmids into a suitable cell type. Typically said cell will not endogenously express nuclear receptors that interact with the response elements used in the reporter plasmid.

Numerous reporter gene systems are known in the art and include, for example, alkaline phosphatase (Berger, J., et al., (1988) Gene 66 1-10; and Kain, SR, (1997) Methods. Mol. Biol. 63 49-60), -galactosidase (see U.S. Patent No. 5,070,012, issued December 3, 1991 to Nolan et al., And Bronstein, I., et al., (1989) J. Chemilum. Biolum. 4 99-111), chloramphenicol acetyltransferase (see Gorman et al., Mol. Cell Biol. (1982) 2 1044-51), -glucuronidase, peroxidase, lactamase (patents U.S. No. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (U.S. Patents 5,221,623; 5,683,888; 5,674,713; 5,650,289; 5,843,746) and naturally occurring fluorescent proteins (Tsien, RY, (1998) Annu. Rev. Biochem. 67 509-44).

The use of chimeras comprising the ligand binding domain (LBD) of the nuclear receptor of interest with a heterologous DNA binding domain (DBD) increases the versatility of cell-based assays by directing the activation of the nuclear receptor in question to elements Defined DNA binding recognized by a defined DNA binding domain (see document W095 / 18380). This assay increases the utility of cell-based co-transfection assays in cases where the biological response or the scanning window using the native DNA binding domain is unsatisfactory.

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In general, the methodology is similar to that used with the basic co-transfection assay, except that the chimeric construct is used instead of the full-length nuclear receptor. As with the full-length nuclear receptor, treatment of cells transfected with an agonist for the LBD of the nuclear receptor increases the transcriptional activity of the heterologous DNA binding domain, which is reflected by an increase in the expression of the reporter gene as described above Typically, for such chimeric constructs, DNA binding domains of defined nuclear receptors, or transcription regulators derived from yeasts or bacteria such as members of the GAL 4 and Lex A / Umud superfamilies are used.

A third cell-based assay useful for exploring compounds of the present invention is a double hybrid mammalian assay that measures the ability of the nuclear hormone receptor to interact with a cofactor in the presence of a ligand (see, for example, the patents for United States No. 5,667,973, 5,283,173 and 5,468,614). The basic approach is to create three plasmid constructs that allow the interaction of the nuclear receptor with the interaction protein to be coupled to a transcriptional reading product within a living cell. The first construct is an expression plasmid to express a fusion protein comprising the interaction protein,

or a part of that protein that contains the interaction domain, fused to a DNA binding domain of GAL4. The second expression plasmid comprises DNA encoding the nuclear receptor of interest fused to a strong transcription activation domain such as VP16, and the third construct comprises the reporter plasmid comprising a reporter gene with a minimal promoter and activation sequences. chain above GAL4.

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Once all three plasmids have been introduced into a cell, the GAL4 DNA binding domain encoded in the first construct allows specific binding of the fusion protein to GAL4 sites upstream of a minimal promoter. However, since the GAL4 DNA binding domain typically has no properties of strong activation of transcription in isolation, expression of the reporter gene occurs only at a low level. In the presence of a ligand, the nuclear receptor fusion protein-VP16 can bind to the interaction GAL4 fusion protein by placing the strong VP16 transcription activator in close proximity to the GAL4 binding sites and the minimum promoter region of the reporter gene This interaction significantly enhances the transcription of the reporter gene that can be measured for various reporter genes as described above. Transcription of the reporter gene is therefore directed by the interaction of the interaction protein and the nuclear receptor of interest in a ligand-dependent mode.

Any compound that is a candidate for FXR activation can be tested by these methods. Generally, the compounds are tested at several different concentrations to optimize the chances of detection and recognition of receptor activation if present. Typically the tests are performed in triplicate and vary within an experimental error by less than 15%. Each experiment is typically repeated three or more times with similar results.

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The activity of the reporter gene can be conveniently normalized to the internal control and the data represented as the activation factor in relation to the untreated cells. A positive control compound (agonist) may be included together with DMSO as the high and low controls for normalization of the test data. Also, antagonistic activity can be measured by determining the ability of a compound to completely inhibit the activity of an agonist.

In addition, the compounds and compositions can be evaluated for their ability to increase or decrease the expression of genes known to be modulated by FXR and other nuclear receptors in vivo, using Northern blotting, RT-PCR or oligonucleotide microseries analysis to analyze RNA levels Western blot analysis can be used to measure the expression of proteins encoded by FXR target genes. Genes that are known to be regulated by FXRs include cholesterol 7 hidro-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol into bile acids, the small heterodimeric binding partner-1 (SHP-1) , the bile salt export pump (BSEP, ABCB11), the bile acid canalicular export protein, the sodium taurocholate co-transport polypeptide (NTCP, SLC10A1) and the bile acid binding intestinal protein (I-BABP ).

There are established animal models for various diseases of direct relevance to the claimed compounds and these can be used to further profile and characterize the claimed compounds.

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These model systems include diabetic dyslipidemia using Zucker rats (fa / fa) or mice (db / db), spontaneous hyperlipidemia using mice deficient in apolipoprotein E (ApoE - / -), tooth-induced hyperlipidemia, using mice deficient in the low density lipoprotein receptor (LDR - / -) and atherosclerosis using both Apo E (- / -) and LDL (- / -) mice fed a western diet (21% fat, 0.05% of cholesterol). In addition, animal models of FXR or LXR (eg, knockout mice) can be used to further evaluate the present compounds and compositions in vivo (see, for example, Sinal, et al., Cell, 102: 731-744 (2000), Peet , et al., Cell, 93: 693-704 (1998)).

F. Methods of use of compounds and compositions

Methods of using the compounds and compositions provided herein are also provided. The methods involve both in vitro and in vivo uses of the compounds and compositions to alter the activity of nuclear receptors, including the activity of FXR and / or orphan nuclear receptors, and for the treatment, prevention, or improvement of one or more symptoms of diseases or disorders that are modulated by the activity of nuclear receptors, including the activity of FXR and / or orphan nuclear receptors, or in which the activity of nuclear receptors is involved, including FXR activity and / or orphan nuclear receptors.

Methods for altering the activity of nuclear receptors, including the activity of FXR, and / or orphan nuclear receptors, are provided by contacting the receptor with one or more compounds or compositions provided herein.

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Methods for reducing cholesterol levels and for modulating cholesterol metabolism and catabolism, absorption of dietary cholesterol (see, for example, International Patent Application Publication No. 00/40965) and reverse cholesterol transport are provided. (See, for example, International Patent Application Publication No. WO 00/78972), all of which involves the activity of FXR. Methods for increasing the expression of the ATP-binding cassette (ABC1) in mammalian cells are also provided using the compounds and compositions provided herein (see, for example, International Patent Application Publication No. WO 00/78972).

Methods of treatment, prevention, or improvement of one or more symptoms of a disease or disorder that affects the levels of cholesterol, triglycerides, or bile acids are provided using the compounds and compositions provided herein. Methods of treatment, prevention, or improvement of one or more symptoms of a disease or disorder that affects lipid metabolism (i.e. lipodystrophy) are also provided. Methods of treatment, prevention, or improvement of one or more forms of hyperlipidemia, including hypercholesterolemia, are provided (see, for example, International Patent Application Publication No. WO 00/57915); hyperlipoproteinemia (see, for example, International Patent Application Publication No. WO 01/60818) and hypertriglyceridemia. The term "hyperlipidemia" refers to the presence of an abnormally high level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, that is, an elevated cholesterol level; (2) hypertriglyceridemia, that is, an elevated triglyceride level; and (3) combined hyperlipidemia, that is, a combination of hypercholesterolemia and hypertriglyceridemia.

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Methods are also provided for the treatment, prevention, or improvement of various pathologies associated with elevated cholesterol levels, including coronary artery disease, pectoral angina, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma.

Methods of treatment, prevention, or improvement of one or more symptoms of dyslipidemia are also provided herein. The term "dyslipidemia" refers to abnormal levels of lipoproteins in blood plasma including reduced and / or elevated levels of lipoproteins (eg, elevated levels of LDL, VLDL and reduced levels of HDL).

Methods of treatment, prevention, or improvement of hyperglycemia or diabetes mellitus are also provided (see, for example, International Patent Application Publication No. WO 01/82917) using the compounds and compositions provided herein. Diabetes mellitus, usually called diabetes, refers to a disease or condition that is generally characterized by metabolic defects in the production and use of glucose that causes a failure in the maintenance of proper blood sugar levels in the body (see, for example, LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. USA 1996)).

In the case of the form of type 2 diabetes, the disease is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects over a wide range of concentrations. This resistance to insulin sensitivity causes insufficient activation by insulin of the uptake, oxidation and storage of glucose in the muscle and inadequate repression by insulin of lipolysis in adipose tissue and of the production and secretion of glucose in the liver (see, for example, Reaven, GM, J. Basic & Clin. Phys. & Pharm. (1998) 9: 387-406 and Flier, J. Ann Rev. Med. (1983) 34: 145-60) . The resulting condition is high blood glucose, which is called "hyperglycemia." Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk of microvascular and macrovascular diseases, including retinopathy (impaired or lost vision due to damage of blood vessels in the eyes); neuropathy (nerve damage and foot problems due to damage of blood vessels to the nervous system); and nephropathy (kidney disease due to damage of blood vessels in the kidneys), hypertension, cerebrovascular disease and coronary heart disease. Therefore, glucose homeostasis control is a critically important approach to the treatment of diabetes.

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Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased triglyceride levels and decreased HDL cholesterol levels, and central and global obesity. The association of insulin resistance with glucose intolerance, an increase in plasma triglyceride levels and a decrease in the concentration of high density lipoprotein cholesterol, hypertension, hyperuricemia, low density lipoprotein particles denser and smaller, and the higher levels of plasminogen activator inhibitor-1 in circulation, has been referred to as "syndrome X" (see, for example, Reaven,

G. M., Physiol. Rev. (1995) 75: 473-486). Accordingly, methods of treatment, prevention, or improvement of any disorder related to insulin resistance are provided including the group of pathologies, conditions or disorders that make up "syndrome X".

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Methods of treatment, prevention, or improvement of obesity, atherosclerosis, lipid disorders, cardiovascular disorders, or gallstone disease are provided (see, for example, International Patent Application Publication No. WO 00 / 37077); acne vulgaris or acneiform skin conditions (see, for example, International Patent Application Publication No. WO 00/49992); Parkinson's disease, inflammation, immune disorders, cancer or Alzheimer's disease (see, for example, International Patent Application Publication No. WO 00/17334); conditions characterized by an impaired function of the epidermal barrier, peripheral occlusive disease, ischemic stroke, or conditions of altered differentiation or proliferation in excess of the epidermis or mucous membranes (see, for example, United States patents No. 6,184,215 and 6,187,814, and International Patent Application Publication No. WO 98/32444).

This document additionally provides methods for the treatment, prevention, or improvement of one or more symptoms of cholestasis, as well as for the treatment of cholestasis complications by administering a compound provided herein.

Cholestasis is typically caused by factors inside the liver (intrahepatic) or outside the liver (extrahepatic) and leads to the accumulation of bile salts, the bilirubin pigment of the bile, and lipids in the bloodstream instead of being removed normally.

Intrahepatic cholestasis is characterized by a generalized blockage of small ducts or by disorders, such as hepatitis, that alter the body's ability to eliminate bile. Intrahepatic cholestasis can also be caused by alcoholic liver disease, primary biliary cirrhosis, cancer that has spread (metastasized) from another part of the body, primary sclerosing cholangitis, gallstones, biliary colic and acute cholecystitis. It can also happen as a complication of surgery, serious injury, cystic fibrosis, infection, or intravenous feeding or it may be drug induced. Cholestasis can also happen as a complication of pregnancy and often develops during the second and third trimesters.

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Extrahepatic cholestasis is most often caused by choledocolithiasis (gallstones), benign bile constrictions (non-cancerous narrowing of the common driver), cholangiocarcinoma (ductal carcinoma) and pancreatic carcinoma. Extrahepatic cholestasis can happen as a side effect of many medications.

Accordingly, the compounds provided herein may be used for the treatment, prevention, or improvement of one or more symptoms of intrahepatic or extrahepatic cholestasis, including without limitation, biliary arthresia, obstetric cholestasis, neonate cholestasis, drug-induced cholestasis, Cholestasis due to Hepatitis C infection, chronic cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

This invention additionally provides methods for treating obesity, as well as for treating the complications of obesity, by administering a compound of the present invention. The terms "obese" and "obesity" refer to, according to the World Health Organization, a body mass index (BMI) greater than 27.8 kg / m2 for men and 27.3 kg / m2 for women (BMI equal to weight (kg) / height (m2)). Obesity is linked to a variety of medical conditions including diabetes and hyperlipidemia. Obesity is also a known risk factor for the development of type 2 diabetes (see, for example, Barrett-Conner, E., Epidemol. Rev. (1989) 11: 172181; and Knowler, et al., Am. J Clin. Nutr. (1991) 53: 15431551).

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The compounds or compositions that can be used to treat obesity or its complications can be identified, formulated, and administered as previously described. Said compound or composition will comprise an antagonist, a partial agonist / antagonist or selective antagonist for FXR that shows a preference of about two to about ten times for FXR compared to another nuclear receptor such as, for example, LXR or  with respect to the potency (IC50, the concentration of compound that achieves 50% of the maximum reduction in transcription activity achieved by the compound of interest observed in the presence of a sub-maximum concentration of the FXR agonist) and / or the efficacy (the percentage of maximum transcription inhibition observed with the compound in question).

G. Combination Therapy

Combination therapy is also contemplated herein using a compound provided herein, or a pharmaceutically acceptable derivative thereof, in combination with one or more of the following: anti-hyperlipidemic agents, agents that raise plasma HDL levels, anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (for example, cholestyramine or colestipol)), low density lipoprotein receptor inducers , clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B12, anti-oxidant vitamins, -blockers, anti-diabetes agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, agonists, antagonists or partial agonists of LXR or , aspirin or derivatives of fibric acid. The compound provided herein, or pharmaceutically acceptable derivative thereof, is administered simultaneously with, before, or after administration of one or more of the above agents. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided.

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Combination therapy includes the administration of a single pharmaceutical dosage formulation containing selective compound for FXR and one or more additional active agents, as well as administration of the selective compound for FXR and each of the active agents in its own dosage formulation. Different pharmaceutical For example, an FXR agonist or antagonist of the present invention and an HMG-CoA reductase inhibitor can be administered to patients together in a single oral dosage composition such as a tablet or capsule, or each agent can be administered in dosage formulations. different oral When different dosage formulations are used, the compounds described herein and one

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or more additional active agents can be administered essentially at the same time, that is, concurrently, or at separately staggered moments, that is, sequentially; It is understood that combination therapy includes all these regimens.

The compound is preferably administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor. The term "HMG-CoA reductase inhibitor" is intended to include all pharmaceutically acceptable salts, esters, acids and lactone forms of compounds that have HMG-CoA reductase inhibitory activity and, therefore, the use of said salts, esters. , free acids and forms of lactone are included within the scope of this invention. Compounds that have inhibitory activity for HMG-CoA reductase can be easily identified using assays well known in the art. For example, suitable assays are described or disclosed in U.S. Patent No. 4,231,938 and WO 84/02131. Examples of suitable HMG-CoA reductase inhibitors include, but are not limited to, lovastatin (MEVACOR®; see U.S. Patent No. 4,231,938); simvastatin (ZOCOR®; see U.S. Patent No. 4,444,784); pravastatin sodium (PRAVACHOL®; see U.S. Patent No. 4,346,227); Fluvastatin sodium (LESCOL®; see US Patent No. 5,354,772); atorvastatin calcium (LIPITOR®, see U.S. Patent No. 5,273,995) and rivastatin (also known as cerivastatin; see U.S. Patent No. 5,177,080). The structural formulas of these and additional HMG-CoA reductase inhibitors that can be used in the methods of the present invention are described on page 87 of M. Yalpani, "Cholesterol Lowering Drugs," Chemistry & Industry, p. 85-89 (February 5, 1996). In presently preferred embodiments, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin.

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Dosage information for HMG-CoA reductase inhibitors is well known in the art, since several HMG-CoA reductase inhibitors are marketed in the United States. In particular, the daily dosage amounts of the HMG-CoA reductase inhibitor may be equal to or similar to the amounts used for anti-hypercholesterolemic treatment and which are described in the Physicians' Desk Reference (PDR). For example, see the 50th Ed. Of the PDR, 1996 (Medical Economics Co); in particular, see page 216, the "Hypolipidemics," sub-heading "HMG-CoA Reductase Inhibitors" heading, and the reference pages cited therein. Preferably, the oral dosage amount of the HMG-CoA reductase inhibitor is about 1 to 200 mg / day and, more preferably, about 5 to 160 mg / day. However, the dosage amounts will vary depending on the potency of the specific HMG-CoA reductase inhibitor used as well as other factors indicated above. An HMG-CoA reductase inhibitor that has sufficiently greater potency can be given at daily dosages below milligrams.

As examples, the daily dosage amount for simvastatin can be selected from 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg; for lovastatin, 10 mg, 20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg; and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosage amount for atorvastatin calcium may be in the range of 1 mg to 160 mg and, more particularly, 5 mg to 80 mg. Oral administration can be in a single dose.

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or in divided doses of two, three, or four times a day, although a single daily dose of the HMG-CoA reductase inhibitor is preferred.

Diabetic patients are prone to suffer from premature development of atherosclerosis and an increased rate of peripheral cardiovascular and vascular diseases. Hyperlipidemia and dyslipidemia are important precipitating factors for these diseases. Hyperlipidemia is a condition usually characterized by an abnormal increase in serum lipid levels (for example, triglycerides and cholesterol) in the bloodstream and is an important risk factor in the development of atherosclerosis and heart disease. See, for example, Wilson, J. et al., (Ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W. B. Sanders Company, Philadelphia, Pa. USA. 1998). Dyslipidemia is an abnormal level of lipoproteins in the blood plasma (for example, elevated levels of LDL, VLDL and reduced levels of HDL), and has been shown to be one of the main contributions to the increased incidence of coronary events and deaths among diabetic subjects (see, for example, Joslin, E. Ann. Chim. Med. (1927), 5: 1061-1079). Epidemiological studies have since confirmed the association and demonstrated a several-fold increase in coronary deaths among diabetic subjects compared to non-diabetic subjects (see, for example, Garcia, M. J. et al., Diabetes (1974),

23: 105-11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997), 5 (4): 294-315).

The methods of the present invention can be used effectively in combination with one or more additional active anti-diabetes agents depending on the desired target therapy (see, for example, Turner, N. et al., Prog. Drug Res. (1998) 51 : 33-94; Haffner, S., Diabetes Care (1998) 21: 160-178; and DeFronzo, R. et al., (Eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Several studies have investigated the benefits of combination therapies with oral agents (see, for example, Mahler, R., J. Clin. Endocrinol. Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, CW, (ed.), CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby-Year Book, Inc., St. Louis, Mo. 1997); Chiasson , J. et al., Ann. Intern. Med. (1994) 121: 928-935; Coniff, R. et al., Clin. Ther. (1997) 19: 16-26; Coniff, R. et al. , Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. et al, Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol (1998) 82 ( 12A): 3U-17U). These studies indicate that the modulation of diabetes and hyperlipidemia can be further improved by the addition of a second agent to the therapeutic regimen.

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An example of combination therapy that modulates (prevents the appearance of associated symptoms or complications) atherosclerosis, is administered with one or more of the following active agents: an antihyperlipidemic agent; an agent that elevates plasma HDL levels; an antihypercholesterolemic agent, such as a cholesterol biosynthesis inhibitor, for example, a hydroxymethylglutaryl (HMG) CoA reductase inhibitor (also known as statins, such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin), inhibitor of HMG-CoA synthase, a squalene epoxidase inhibitor, or a squalene synthetase inhibitor (also known as squalene synthase inhibitor); an acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitor, such as melinamide; probucol; nicotinic acid and salts thereof and niacinamide; a cholesterol absorption inhibitor, such as -sitosterol; a bile acid sequestering anion exchange resin, such as cholestyramine, colestipol or dialkylaminoalkyl derivatives of a crosslinked dextran; an inducer of the LDL receptor (low density lipoprotein); fibrates, such as clofibrate, bezafibrate, fenofibrate, and gemfibrizol; vitamin B6 (also known as pyridoxine) and pharmaceutically acceptable salts thereof, such as the HCl salt; vitamin B12 (also known as cyanocobalamin); vitamin B3 (also known as nicotinic acid and niacinamide, supra); antioxidant vitamins, such as vitamin C and E and beta carotene; a beta blocker; agonists, antagonists or partial agonists of LXR or , an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; and a platelet aggregation inhibitor, such as fibrinogen receptor antagonists (i.e., glycoprotein fibrinogen receptor IIb / IIa antagonists) and aspirin.

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Another example of combination therapy can be seen in the modulation of diabetes (or treatment of diabetes and its symptoms, complications, and related disorders) with, for example, sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glinase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-PPAR activators of PPAR,  and PPAR; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulfate ester, DHEA-SO4); antiglucocorticoids; TNF inhibitors; luglucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analogue of the human hormone amylin), other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide), insulin, as well as the active agents tested previously to treat atherosclerosis.

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Another example of combination therapy is the co-administration of the compound or composition provided herein with compounds or compositions for treating obesity or obesity-related disorders, where the methods can be used effectively in combination with, for example, phenylpropanolamine, Phentermine, diethylpropion, mazindole; fenfluramine, dexfenfluramine, phentiramine, reno3 adrenoceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), agonists, antagonists and partial agonists of LXR or , and leptins. Other agents used to treat obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholekinkinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptors, melanocyte stimulating hormone, corticotropin releasing factor, galanin and acid gamma aminobutyric acid (GABA).

Other examples of a combination therapy can be seen in the treatment of cholestasis, where the compounds of the invention can be combined with Actigall (ursodeoxycholic acid - UDCA), corticosteroids, anti-infectious agents (Rifampin, Rifadine, Rimactan), anti- viral, vitamin D, vitamin A, phenobarbital, cholestyramine, UV light, antihistamines, oral opioid receptor antagonists and bisphosphates, for the treatment, prevention, or improvement of one or more symptoms of intrahepatic or extrahepatic cholestasis. Dosage information for these agents is well known in the art.

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The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. The starting materials in the following synthesis examples are available from commercial sources.

or through bibliography procedures. All commercially available compounds were used without further purification unless otherwise indicated. CDCl3 (99.8% D, Cambridge Isotope Laboratories) was used in all the indicated experiments. Proton nuclear magnetic resonance (NMR) spectra (1H) were recorded on a Bruker Advance 400 MHz NMR spectrometer. Significant peaks are tabulated and typically include: the number of protons, and the multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; sa, wide singlet). Chemical shifts are presented as parts per million () relative to tetramethylsilane. Low resolution (MS) mass spectra were obtained as electrospray ionization (ESI) mass spectra, which were recorded on a Perkin-Elmer SCIEX HPLC / MS instrument using reverse phase conditions (acetonitrile / water, trifluoroacetic acid 0.05%). Flash chromatography was performed using Merck silica gel 60 (230-400 mesh) following the conventional protocol (Still et al. J. Org. Chem. 1978, 43, 2923).

EXAMPLE 1 PREPARATION OF METHYL ESTER OF THE ACID 2- (2CLOROPROPIONILAMINO) BENZOICO AND RELATED COMPOUNDS

A. To methyl anthranilate (5 g, 33.1 mmol) while stirring in DCM at 0 ° C in N2 DIEA (5.1 g, 39.7 mmol) was added in one portion followed by the dropwise addition of 2-chloropropionyl chloride ( 4.2 g, 33.1 mmol). The reaction was allowed to stir at 0 ° C for 30 min., Then heated to room temperature, stirring for an additional 3 h. The reaction was treated with saturated aqueous NaHCO3 solution and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted twice more with DCM (25 ml). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to yield the desired product (7.75 g, 97% yield), which was used without further purification. 1 H NMR (CDCl 3):  11.8 (a, 1 H), 8.72 (dd, 1 H), 8.08 (dd, 1 H), 7.58 (m, 1 H), 7.15 (m, 1 H ), 4.56 (c, 1H), 3.97 (s, 3H), 1.85 (d, 3H).

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B. Similarly, but replacing the methyl anthranilate with 2-amino-5-bromobenzoic acid methyl ester, the following compound was prepared:

5-Bromo-2- (2-chloropropionylamino) -benzoic acid methyl ester; 1H NMR (CDCl3):  11.77 (width, 1H), 8.64 (d, 1H), 8.18 (d, 1H), 7.65 (dd, 1H), 4.53 (c, 1H ), 3.97 (s, 3H), 1.82 (d, 3H); MS (ESI) 320 (MH +).

EXAMPLE 2

PREPARATION OF ACID 2- (2-CHLOROPROPIONYLAMINE) BENZOIC

To the 2- (2-chloro-propionylamino) benzoic acid methyl ester (7.75 g, 32.1 mmol) with stirring in THF (40 ml) was added 1 M LiOH / H2O (40 ml). The reaction was allowed to stir at 50 ° C for 3 h. After this period, the reaction was concentrated in vacuo to yield a crude residue that was acidified with 1N HCl. The resulting suspension was then diluted with EtOAc and washed with water (3 x 50 mL). The organic layer was then washed with brine (25 ml), dried over MgSO4, and concentrated in vacuo to yield the crude acid. The crude material was purified by flash chromatography (silica gel, 80% EtOAc / Hex) to yield the desired product as an off-white solid (7.1 g, 97% yield). 1 H NMR (CDCl 3):  8.6 (d, 1 H), 8.12 (d, 1 H), 7.61 (t, 1 H), 7.57 (t, 1 H), 4.89 (a, 1 H ), 4.65 (t, 1 H), 1.78 (d, 3 H).

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EXAMPLE 3

PREPARATION OF 2- (1-CHLOROETHYL) -3- (4-METOXYPHENYL) -3H

QUINAZOLIN-4-ONA AND RELATED COMPOUNDS

A. To a stirring suspension of 2- (2-chloropropionylamino) -benzoic acid (5 g, 22 mmol) and p-anisidine (2.7 g, 22 mmol) in 100 ml of toluene, phosphorus trichloride was added dropwise (PCI3) (3.02 g, 22 mmol) for 15 minutes. When the addition was complete, the reaction was heated at reflux for 3 h and cooled to room temperature and treated with 5 ml water. The resulting mixture was concentrated in vacuo to yield a semi-solid residue that was treated with 1N HCl and extracted twice with 200 ml portions of EtOAc. The organic extracts were combined, washed with brine, dried over MgSO4, and concentrated in vacuo to yield the crude product that was purified by column chromatography (silica gel, EtOAc / Hex 4: 1) (4.96 g , 72% yield). 1H NMR (CDCl3):  8.31 (m, 1H), 7.82 (m, 2H), 7.54 (m, 1H), 7.43 (dd, 1H), 7.09 (m, 3H ), 4.66 (c, 1H), 3.91 (s, 3H), 1.89 (d, 3H).

B. Similarly, but replacing p-anisidine with the appropriate starting material, the following compounds were prepared:

2- (1-Chloroethyl) -3- (4-methylphenyl) -3H-quinazolin-4-one; 1 H NMR (CDCl 3):  8.29 (d, 1 H), 7.80 (d, 2 H), 7.52 (m, 1 H), 7.38 (s, 2 H), 7.34 (d, 1 H ), 7.07 (m, 1H), 4.62 (c, 1H), 2.46 (s, 3H), 1.87 (d, 3H); MS (ESI) 299 (MH +);

3- (4-bromophenyl) -2- (1-chloroethyl) -3H-quinazolin-4-one; 1 H NMR (CDCl 3): ,2 8.28 (d, 1 H), 7.81 (m, 2 H), 7.70 (m, 2 H), 7.54 (m, 1 H), 7.39 (m, 1 H ), 7.08 (m, 1H), 4.55 (c, 1H), 1.88 (d, 3H); MS (ESI) 365 (MH +); Y

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2- (1-Chloroethyl) -3- (2,4-dimethylphenyl) -3H-quinazolin-4one; 1H NMR (CDCl3):  8.33 (d, 1H), 7.83 (m, 2H), 7.54 (m, 1H), 7.26 (m, 2H), 6.95 (d, 1H ), 4.73 (c, 1H), 2.44 (s, 3H), 2.22 (s, 1.5H), 2.06 (s, 1.5H), 1.89 (m, 1H) ; MS (ESI) 313 (MH +).

C. In a manner similar to that described above in paragraph A, but replacing 2- (2-chloropropionylamino) benzoic acid with 5-bromo-2- (2-chloropropionylamino) benzoic acid and p-anisidine with 4-methyl-phenylamine, He prepared the following compound:

6-Bromo-2- (1-chloroethyl) -3-p-tolyl-3H-quinolin-4-one; 1H NMR (CDCl3): ,40 8.40 (m, 1H), 7.87 (m, 1H), 7.67 (d, 1H), 7.37 (m, 3H), 7.04 (m, 1H ), 4.59 (c, 1H), 2.46 (s, 3H), 1.84 (d, 3H); MS (ESI) 377 (MH +).

EXAMPLE 4 PREPARATION OF BENCYLIC ACID ESTER [3- (4-METOXIFENIL) 4-OXO-3,4-DIHYDROQUINAZOLIN-2-ILMETILE] -CARBAMIC AND COMPOUNDS RELATED

A. To a stirring suspension of 2- (2-benzyloxycarbonylamino-acetylamino) -benzoic acid (2 g, 6.1 mmol) in THF (100 ml) was added carbonyl diimidizol (CDI) (1.0 g, 6.2 mmol ) and stirred for 1 h at room temperature under a nitrogen atmosphere. After 1 h, the reaction was treated with p-anisidine (0.73 g, 6.1 mmol) and refluxed for 16 h. The reaction was cooled to room temperature and concentrated in vacuo to yield a crude residue that was dissolved in EtOAc (50 ml). Then, the mixture was washed with saturated NaHCO3 (50 ml) followed by brine (25 ml). The organic layer was dried over MgSO4 and concentrated in vacuo to yield the crude product that was purified by flash chromatography (silica gel, EtOAc / Hex 4: 1) (1.21 g, 48% yield). 1 H NMR (CDCl 3):  8.26 (m, 1H), 7.72 (m, 2H), 7.47 (m, 1H), 7.34 (m, 5H), 7.19 (m, 2H ), 7.03 (m, 2H), 6.28 (width, 1H), 5.10 (s, 2H), 4.50 (s, 2H), 3.85 (s, 3H).

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B. Similarly, but replacing p-anisidine with 2,4-dimethylaniline, the following compound was prepared:

[3- (2,4-Dimethylphenyl) -4-oxo3,4-dihydroquinazolin-2-ylmethyl] -carbamic acid benzyl ester; MS (ESI) 414 (MH +).

EXAMPLE 5 PREPARATION OF 3- (4-METOXIFENIL) -2- (1-METHYLAMINE) -3HQUINAZOLIN-4-ONA AND RELATED COMPOUNDS

A. To pure 2- (1-chloroethyl) -3- (4-methoxyphenyl) -3H-quinazolin4-one (1.0 g, 3.2 mmol) in a tightly sealed tube, 40 ml of a solution of methylamine (1 M in THF, 40 mmol). The tube was tightly sealed and heated at 110 ° C for 16 h. The resulting solution was cooled to room temperature and concentrated in vacuo to yield the crude product that was purified by flash chromatography (5% MeOH / DCM, silica gel) to yield the title compound (0.97 g, yield of 99%) 1H NMR (CD3OD): ,2 8.28 (m, 1H), 7.93 (m, 1H), 7.86 (m, 1H), 7.65 (m, 1H), 7.43 (m, 1H ) 7.33 (m, 1H), 7.19 (m, 2H), 4.09 (c, 1H), 3.92 (s, 3H), 2.75 (s, 3H), 1.51 ( d, 3H).

B. Similarly, but replacing 2- (1-chloroethyl) 3- (4-methoxyphenyl) -3H-quinazolin-4-one with the appropriate starting material, the following compounds were prepared:

2- (1-Methylaminoethyl) -3-p-tolyl-3H-quinazolin-4-one; 1H NMR (CD3OD): ,2 8.28 (d, 1H), 7.77 (m, 1H), 7.71 (m, 1H), 7.47 (m, 1H), 7.36 (m, 2H ), 7.12 (m, 2H), 3.37 (c, 1H), 2.46 (s, 3H), 2.28 (s, 3H), 1.24 (d, 3H); MS (ESI) 294 (MH +);

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6-Bromo-2- (1-methylaminoethyl) -3-p-tolyl-3H-quinazolin-4one; 1H NMR (CD3OD): ,3 8.39 (d, 1H), 7.84 (m, 1H), 7.59 (d, 1H), 7.37 (m, 2H), 7.11 (m, 2H ), 3.36 (c, 1H), 2.46 (s, 3H), 2.26 (s, 3H), 1.57 (width, 1H), 1.23 (d, 3H); MS (ESI) 317 (MH +);

3- (2,4-dimethylphenyl) -2- (1-methylaminoethyl) -3H-quinazolin4-one; 1H NMR (CD3OD): ,2 8.29 (d, 1H), 7.75 (m, 2H), 7.47 (t, 1H), 7.14 (s, 1H), 6.85 (d, 2H ), 3.38 (c, 1H), 2.39 (s, 6H), 2.29 (s, 3H), 1.25 (d, 3H); MS (ESI) 308 (MH +); Y

3- (4-methoxyphenyl) -2-methylaminomethyl-3H-quinazolin-4-one; 1H NMR (CD3OD): ,2 8.27 (d, 1H), 7.93 (m, 1H), 7.86 (d, 1H), 7.65 (t, 1H), 7.43 (m, 1H ), 7.33 (m, 1H), 7.19 (m, 2H), 4.08 (s, 2H), 3.92 (s, 3H), 2.74 (s, 3H); MS (ESI) 296 (MH +).

C. Similarly, but with the appropriate starting materials, the following compound was prepared:

3- (4-methoxyphenyl) -8-methyl-2- (1-methylaminoethyl) -3Hquinazolin-4-one; MS (ESI) 324 (MH +).

D. In a manner similar to that described above in Example 1, but replacing methyl anthranilate with the appropriate intermediate starting material, and in a manner similar to that described above in paragraph A, the following compounds were prepared:

3- (4-methoxyphenyl) -6-methyl-2- (1-methylaminoethyl) -3Hquinazolin-4-one; MS (ESI) 324 (MH +); 3- (4-methoxyphenyl) -7-methyl-2- (1-methylaminoethyl) -3Hquinazolin-4-one; MS (ESI) 324 (MH +); 8-methoxy-3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3Hquinazolin-4-one; MS (ESI) 340 (MH +); 5-methoxy-3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3Hquinazolin-4-one; MS (ESI) 340 (MH +); and 6-methoxy-3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H

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quinazolin-4-one; MS (ESI) 340 (MH +).

EXAMPLE 6

PREPARATION OF 2-AMINOMETIL-3- (4-METOXIFENIL) -3H-QUINAZOLIN

4-ONA

In an oven-dried flask that was purged with nitrogen, 3- (4-methyloxyphenyl) -4-oxo3,4-dihydroquinazolin-2-ylmethyl] -carbamic acid benzyl ester (1.0 g, 2.4 mmol ). The starting material was diluted with EtOH sprayed with nitrogen (25 ml) while maintaining a nitrogen atmosphere. To the reaction mixture was added 10% Pd / C (150 mg) and the reaction was sealed with a separation. The sealed reaction was then purged with hydrogen by placing a syringe equipped with a balloon filled with hydrogen gas through the separation. The reaction was vigorously stirred while inserting an additional needle into the separations to thoroughly wash the atmosphere with hydrogen. With a balloon filled with hydrogen at the site, the reaction was allowed to stir for 3 h, after which it was concentrated in vacuo to yield a crude material that was purified by flash chromatography (silica gel, 10% MeOH / DCM ) (0.67 g, 100% yield). 1H NMR (CD3OD):  8.23 (m, 1H), 7.87 (m, 1H), 7.80 (m, 1H), 7.56 (m, 1H), 7.13 (m, 2H ), 7.01 (m, 2H), 3.90 (s, 3H), 3.51 (s, 2H); MS (ESI) 282 (MH +).

EXAMPLE 7

PREPARATION OF 4-TERC-BUTIL-N- {1- [3- (4-METOXIFENIL) -4-OXO

3,4-DIHIDROQUINAZOLIN-2-IL] ETIL} -N-METHYLBENZENOSULPHONAMIDE AND

RELATED COMPOUNDS

A. To a suspension of 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one (50 mg, 0.16 mmol) with stirring in 2 ml of DCM, TEA (19 mg, 0.19 mmol) followed by the addition of pure 4-tert-butylbenzenesulfonyl chloride (37 mg, 0.16 mmol). The reaction was allowed to stir at room temperature for 2 h, then treated with PS-tris-amine resin (100 mg). The reaction was allowed to stand for 15 min. at room temperature, after which the resin was removed by filtration. The filtrate was concentrated in vacuo to yield the crude product. The crude residue was purified by flash chromatography (silica gel, 50% EtOAc / Hex) to yield the desired product as an off-white powder (74 mg, 92% yield). 1H NMR (CDCl3): ,1 8.15 (d, 1H), 7.55 (s, 1H), 7.39 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H ), 7.09 (m, 1H), 6.70 (m, 2H), 4.90 (c, 1H), 4.83 (s, 3H), 3.11 (s, 3H), 1.22 (d, 3H), 1.09 (s, 9H); MS (ESI) 506 (MH +).

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B. Similarly, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with the appropriate starting material, the following compounds were prepared:

4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 1H NMR (CDCl3):  8.22 (m, 1H), 7.63 (m, 1H), 7.51 (m, 2H), 7.44 (m, 3H), 7.33 (m, 2H ), 7.23 (m, 2H), 7.06 (m, 1H), 4.95 (c, 1H), 3.19 (s, 3H), 2.48 (s, 3H), 1.30 (d, 3H), 1.16 (s, 9H); MS (ESI) 490 (MH +);

4-tert-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; (mixture of rotamers) 1 H NMR (CDCl 3):  8.30 (m, 1H), 7.72 (m, 1H), 7.56 (m, 4H), 7.38 (m, 2H), 7, 30 (m, 2H), 7.21 (m, 1H), 5.03 (m, 1H), 3.15 (s, 1.5H), 3.01 (s, 1.5H), 2.47 (s, 1.5H), 2.45 (s, 1.5H), 2.26 (s, 1.5H), 2.04 (s, 1.5H), 1.31 (s, 4.5H ), 1.24 (m, 3H), 1.21 (s, 4.5H); MS (ESI) 504 (MH +);

4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1H NMR (CDCl3): ,5 7.58 (d, 1H), 7.50 (d, 2H), 7.47 (m, 1H), 7.24 (m, 4H), 7.17 (m, 1H ), 7.06 (m, 2H), 4.96 (c, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.15 (s, 3H), 1.28 (d, 3H), 1.18 (s, 9H); MS (ESI) 536 (MH +);

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4-tert-butyl-N- [1- (6-methoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; 1 H NMR (CDCl 3): ,5 7.58 (d, 1 H), 7.50 (d, 2 H), 7.44 (m, 1 H), 7.34 (m, 1 H), 7.24 (m, 5 H ), 7.05 (m, 1H), 4.93 (c, 1H), 3.88 (s, 3H), 3.15 (s, 3H), 2.48 (s, 3H), 1.28 (d, 3H), 1.18 (s, 9H); MS (ESI) 520 (MH +);

4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 1H NMR (CDCl3):  8.22 (m, 1H), 7.63 (m, 1H), 7.51 (m, 2H), 7.44 (m, 3H), 7.33 (t, 2H ), 7.22 (m, 2H), 7.06 (m, 1H), 4.95 (c, 1H), 3.19 (s, 3H), 2.48 (s, 3H), 1.30 (d, 3H), 1.16 (s, 9H); MS (ESI) 490 (MH +);

4-tert-butyl-N-methyl-N- [1- (3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 1H NMR (CDCl3):  8.25 (m, 1H), 7.76 (d, 2H), 7.52 (m, 1H), 7.45 (m, 3H), 5.53 (c, 1H ), 3.84 (s, 3H), 2.81 (s, 3H), 1.41 (d, 3H), 1.27 (s, 9H); MS (ESI) 414 (MH +);

4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -benzamide; 1H NMR (CDCl3):  8.28 (m, 1H), 7.76 (t, 1H), 7.69 (d, 1H), 7.48 (m, 2H), 7.36 (m, 4H ), 7.28 (m, 1H), 7.19 (m, 1H), 6.96 (m, 1H), 5.43 (c, 1H), 3.10 (s, 3H), 2.41 (s, 3H), 1.49 (d, 3H), 1.31 (s, 9H); MS (ESI) 454 (MH +); Y

N- [1- (6-Bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzenesulfonamide; MS (ESI) 568 (MH +).

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C. In a manner similar to that described above in paragraph B, but replacing the 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; (mixture of rotamers) 1 H NMR (CDCl 3):  8.26 (m, 1H), 7.71 (m, 1H), 7.51 (m, 4H), 7.34 (m, 2H), 7, 18 (m, 3H), 5.0 (m, 1H), 3.11 (s, 1.5H), 2.97 (s, 1.5H), 2.85 (m, 1H), 2.44 (s, 1.5H), 2.42 (s, 1.5H), 2.19 (s, 1.5H), 2.01 (s, 1.5H), 1.21 (m, 6H), 1.12 (m, 3 H); MS (ESI) 490 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; (mixture of rotamers) 1 H NMR (CDCl 3):  8.27 (m, 1H), 7.68 (m, 3H), 7.56 (m, 6H), 7.31 (m, 1H), 7, 19 (m, 1H), 6.98 (m, 1H), 5.04 (m, 1H), 3.17 (s, 1.5H), 3.03 (s, 1.5H), 2.45 (s, 1.5H), 2.44 (s, 1.5H), 2.22 (s, 1.5H), 2.02 (s, 1.5H), 1.24 (m, 3H); MS (ESI) 524 (MH +);

Quinoline-8-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; (mixture of rotamers) 1H NMR (CDCl3):  8.56 (m, 1H), 8.49 (m, 0.5H), 8.34 (m, 1H), 8.19 (m, 1H), 7.97 (m, 1H), 7.89 (m, 0.5H), 7.77 (m, 1H), 7.54 (m, 3H), 7.40 (m, 1H), 7.31 (m, 1H), 7.22 (m, 1H), 7.10 (m, 1H), 5.66 (m, 1H), 3.32 (s, 3H), 2.48 (m, 3H) , 2.10 (m, 3H), 1.18 (m, 3H); MS (ESI) 499 (MH +);

N- [1- (6-Bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-isopropyl-N-methylbenzenesulfonamide; MS (ESI) 554 (MH +);

Biphenyl-4-sulfonic acid [1- (6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2yl) ethyl] methylamide; MS (ESI) 588 (MH +);

image111

Benzo [1,3] dioxol-5-carboxylic acid [1- (6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2yl) ethyl] methylamide; MS (ESI) 520 (MH +); Y

N- [1- (6-Bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzamide; MS (ESI) 532 (MH +).

D. In a manner similar to that described above in paragraph A, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

Nonanoic acid {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 450 (MH +);

4-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 444 (MH +);

4-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 480 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 458 (MH +);

N- {1- [3- (4-Methoxyphenyl) -4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-terephthalamic acid methyl ester; MS (ESI) 472 (MH +);

2-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 444 (MH +);

3-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 444 (MH +);

N- {1- [3- (4-Methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 464 (MH +); and 4-cyano-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS

image112

(ESI) 475 (MH +).

E. 4-Cyano-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide, prepared as described above in paragraph D , was hydrolyzed with concentrated HCI at reflux to produce 4 - ({1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -methyl-sulfamoyl) -benzoic acid; MS (ESI) 494 (MH +).

F. In a manner similar to that described above in paragraph A, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 2- (1-methylaminoethyl) 3-p- Tolyl-3H-quinazolin-4-one and 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

benzo [1,3] dioxol-5-carboxylic acid methyl- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2yl) ethyl] amide; MS (ESI) 442 (MH +);

4-isopropyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 476 (MH +); Y

Biphenyl-4-sulfonic acid methyl- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2yl) ethyl] amide; MS (ESI) 510 (MH +).

G. In a manner similar to that described above in paragraph A, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 2-aminomethyl-3- (4-methoxyphenyl) -3H -quinazolin-4-one and 4-tert-butyl benzenesulfonyl chloride with p-toluenesulfonyl chloride, the following compound was prepared:

N- [3- (4-Methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methylbenzenesulfonamide; MS (ESI) 436 (MH +).

H. In a manner similar to that described above in paragraph G, but replacing p-toluenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

image113

4-tert-butyl-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzenesulfonamide; MS (ESI) 478 (MH +);

N- [3- (4-Methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] benzamide; MS (ESI) 386 (MH +);

4-chloro-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 420 (MH +);

3-methoxy-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 416 (MH +);

4-methoxy-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 416 (MH +);

4-tert-butyl-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 442 (MH +);

N- [3- (4-Methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -terephthalamic acid methyl ester; MS (ESI) 444 (MH +);

2,4-dichloro-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 454 (MH +);

4-methoxy-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzenesulfonamide; MS (ESI) 452 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] amide; MS (ESI) 430 (MH +);

Nonanoic acid [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] amide; MS (ESI) 422 (MH +); Y

4-chloro-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzenesulfonamide; MS (ESI) 456 (MH +).

I. The benzyl ester of [3- (2,4-dimethylphenyl) -4oxo-3,4-dihydroquinazolin-2-ylmethyl] carbamic acid, prepared above in Example 4, was hydrogenated in a manner similar to that described above in Example 6, and then condensed, as described above in paragraph A, with benzenesulfonyl chloride to produce N [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] benzenesulfonamide ; MS (ESI) 420 (MH +).

image114

J. In a manner similar to that described above in paragraph I, but replacing the benzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methylbenzenesulfonamide; MS (ESI) 434 (MH +);

4-tert-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzenesulfonamide; MS (ESI) 476 (MH +);

N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methoxy-benzenesulfonamide; MS (ESI) 450 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] benzamide; MS (ESI) 384 (MH +);

4-tert-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 440 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] amide; MS (ESI) 428 (MH +);

2,4-dichloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzamide; MS (ESI) 452 (MH +); Y

N- [3- (2,4-Dimethylphenyl) -4-oxo3,4-dihydroquinazolin-2-ylmethyl] -terephthalamic acid methyl ester; MS (ESI) 442 (MH +).

K. In a manner similar to that described above in paragraph A, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 3- (2,4-dimethylphenyl) 2- (1-Methylaminoethyl) -3H-quinazolin-4-one and replacing the 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

image115

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; MS (ESI) 478 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 456 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-terephthalamic acid methyl ester; MS (ESI) 470 (MH +);

Naphthalene-1-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 498 (MH +);

Naphthalene-2-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 498 (MH +);

2-Naphthalen-1-yl-ethanesulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 526 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2, N-dimethylbenzenesulfonamide; MS (ESI) 462 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -3, N-dimethylbenzenesulfonamide; MS (ESI) 462 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 462 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methyl-C-phenyl-methanesulfonamide; MS (ESI) 462 (MH +);

4-acetyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 490 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methyl-3-trifluoromethylbenzenesulfonamide; MS (ESI) 516 (MH +);

image116

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methyl-4-trifluoromethoxy-benzenesulfonamide; MS (ESI) 532 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2,5, N-trimethylbenzenesulfonamide; MS (ESI) 476 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -3,4-dimethoxy-N-methylbenzenesulfonamide; MS (ESI) 508 (MH +);

N- [4 - ({1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -methyl-sulfamoyl) -phenyl] acetamide; MS (ESI) 505 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2,4,6, N-tetramethylbenzenesulfonamide; MS (ESI) 490 (MH +);

2-Phenyl-ethenesulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 474 (MH +);

2,2,5,6,8-pentamethyl-chroman-7sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 574 (MH +);

Thiophene-2-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 454 (MH +);

C- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-yl) -N- {1- [3 (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin -2-yl] ethyl} -methyl-methanesulfonamide; MS (ESI) 522 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -3,4-difluoro-N-methylbenzenesulfonamide; MS (ESI) 484 (MH +);

3-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2, N-dimethylbenzenesulfonamide; MS (ESI) 496 (MH +);

image117

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -5-fluoro-2, N-dimethylbenzenesulfonamide; MS (ESI) 480 (MH +);

3,5-Dimethyl-isoxazol-4sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 467 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 516 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -3-fluoro-N-methylbenzenesulfonamide; MS (ESI) 466 (MH +);

2,4,6-trichloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 550 (MH +);

3-chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -4-fluoro-Nmethylbenzenesulfonamide; MS (ESI) 500 (MH +);

2-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 482 (MH +);

5-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -2-methoxy-Nmethylbenzenesulfonamide; MS (ESI) 512 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2,5-dimethoxy-N-methylbenzenesulfonamide; MS (ESI) 508 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2,3,4-trifluoro-N-methylbenzenesulfonamide; MS (ESI) 502 (MH +);

3-chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 482 (MH +);

image118

4-cyano-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 473 (MH +);

4-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 504 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4- (1,1-dimethyl-propyl) -N-methylbenzenesulfonamide; MS (ESI) 518 (MH +);

4-butoxy-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +);

N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -3-methoxy-N-methylbenzenesulfonamide; MS (ESI) 478 (MH +);

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2-methoxy-4, N-dimethylbenzenesulfonamide; MS (ESI) 492 (MH +);

4-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -2,5, Ntrimethylbenzenesulfonamide; MS (ESI) 510 (MH +); Y

N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methyl-methanesulfonamide; MS (ESI) 386 (MH +).

L. In a manner similar to that described above in paragraph A, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 3-methyl-2- (1-methylaminoethyl) -3H -quinazolin-4-one and replacing the 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N-methyl-N- [1- (3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 400 (MH +);

image119

Biphenyl-4-sulfonic acid methyl- [1- (3-methyl-4-oxo-3,4-dihydroquinazolin-2yl) ethyl] amide; MS (ESI) 434 (MH +);

4-methoxy-N-methyl-N- [1- (3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 388 (MH +); Y

4-Chloro-N-methyl-N- [1- (3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 392 (MH +).

M. In a manner similar to that described above, 3 (4-methoxyphenyl) -8-methyl-2- (1-methylaminoethyl) -3H-quinazolin-4one, prepared above in Example 5, was condensed with 4- chloride. tert-butylbenzenesulfonyl to produce 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +).

N. In a manner similar to that described above in paragraph M, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 506 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 540 (MH +);

N- {1- [3- (4-Methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 478 (MH +);

4-methoxy-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 494 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 472 (MH +);

image120

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 484 (MH +);

4-butyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +);

N- {1- [3- (4-Methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-4trifluoromethylbenzenesulfonamide; MS (ESI) 532 (MH +); Y

2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 566 (MH +).

O. In a manner similar to that described above in paragraph M, but replacing 2-amino-3-methylbenzoic acid as intermediate starting material at a previous stage with 2-amino-6-methylbenzoic acid, the following compound was prepared:

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +).

P. In a manner similar to that described above in paragraph O, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 506 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 540 (MH +); N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3,4

image121

dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide;

MS (ESI) 478 (MH +); 4-methoxy-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-ethylbenzenesulfonamide;

MS (ESI) 494 (MH +); {1- [3- (4-Methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} methylamide

benzo [1,3] dioxol-5-carboxylic; MS (ESI) 472 (MH +); 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS

(ESI) 484 (MH +); 4-butyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N

methylbenzenesulfonamide; MS (ESI) 520 (MH +); N- {1- [3- (4-Methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methyl-4

trifluoromethylbenzenesulfonamide; MS (ESI) 532 (MH +); and 2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N

methylbenzenesulfonamide; MS (ESI) 566 (MH +).

Q. In a manner similar to that described above in paragraph M, but replacing 2-amino-3-methylbenzoic acid as intermediate starting material at a previous stage with 2-amino-4-chlorobenzoic acid, the following compound was prepared:

4-tert-butyl-N- {1- [7-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide; MS (ESI) 541 (MH +).

A. In a manner similar to that described above in paragraph Q, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material,

image122

The following compounds were prepared: N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N

methylbenzenesulfonamide; MS (ESI) 526 (MH +); {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} methylamide acid

biphenyl-4-sulfonic; MS (ESI) 560 (MH +); N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N

methylbenzenesulfonamide; MS (ESI) 514 (MH +); N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N

methylbenzenesulfonamide; MS (ESI) 484 (MH +); N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -4, N

dimethylbenzenesulfonamide; MS (ESI) 498 (MH +);

N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 552 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [7-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 492 (MH +); Y

4-tert-butyl-N- {1- [7-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 504 (MH +).

S. In a manner similar to that described above in paragraph M, but replacing 2-amino-3-methylbenzoic acid as intermediate starting material at a previous stage with the appropriate intermediate starting material, the following compounds were prepared:

4-tert-butyl-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide; MS (ESI) 540 (MH +); Y

image123

4-tert-butyl-N- {1- [8-chloro-3- (4-methoxyphenyl) -4-oxo-3,

4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide; MS (ESI) 540 (MH +).

T. In a manner similar to that described above in paragraph S, but replacing 4-tert-butylbenzenesulfonyl chloride, the following compounds were prepared:

N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-Nmethylbenzenesulfonamide; MS (ESI) 526 (MH +);

Biphenyl-4-sulfonic acid {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 560 (MH +);

N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-Nmethylbenzenesulfonamide; MS (ESI) 514 (MH +);

N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 484 (MH +);

N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 498 (MH +);

N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 552 (MH +);

2,4,6-trichloro-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 586 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 492 (MH +);

4-tert-butyl-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 504

image124

(MH +); {1- [8-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} methylamide acid

benzo [1,3] dioxol-5-carboxylic; MS (ESI) 492 (MH +); 4-tert-butyl-N- {1- [8-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS

(ESI) 504 (MH +); N- {1- [8-Chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N

methylbenzenesulfonamide; MS (ESI) 526 (MH +); and {1- [8-chloro-3- (4-methoxyphenyl) -4-oxo-3,4

Biphenyl-4 acid dihydroquinazolin-2-yl] ethyl} methylamide

sulfonic; MS (ESI) 560 (MH +).

U. In a manner similar to that described above in paragraph A, 3- (4-methoxyphenyl) -7-methyl-2- (1-methylaminoethyl) -3H-quinazolin-4-one, prepared above in the

Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to produce 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2 -yl] ethyl} -N-ethylbenzenesulfonamide;

MS (ESI) 520 (MH +).

V. In a manner similar to that described above in paragraph U, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,

4-dihydroquinazolin-2-yl] ethyl} -N

methylbenzenesulfonamide; MS (ESI) 506 (MH +); {1- [3- (4-Methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} methylamide

biphenyl-4-sulfonic; MS (ESI) 540 (MH +); N- {1- [3- (4-Methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -4, Ndimethylbenzenesulfonamide; MS (ESI) 478 (MH +);

image125

4-methoxy-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 494 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 472 (MH +);

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 484 (MH +);

4-butyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +);

N- {1- [3- (4-Methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 532 (MH +); Y

2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 566 (MH +).

W. In a manner similar to that described above in paragraph A, 8-methoxy-3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to produce 4-tert-butyl-N- {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 536 (MH +).

X. In a manner similar to that described above in paragraph W, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 522 (MH +);

image126

Biphenyl-4-sulfonic acid {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 556 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 488 (MH +); Y

4-tert-butyl-N- {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 500 (MH +).

Y. In a manner similar to that described above in paragraph A, 5-methoxy-3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one, prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to produce 4-tert-butyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 536 (MH +).

Z. In a manner similar to that described above in paragraph Y, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 522 (MH +);

Biphenyl-4-sulfonic acid {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 556 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 488 (MH +); Y

4-tert-butyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 500 (MH +).

image127

AA In a manner similar to that described above in paragraph A, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 6-methoxy-3- (4-methoxyphenyl) -2- ( 1-Methylaminoethyl) -3H-quinazolin-4-one and 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 522 (MH +);

Biphenyl-4-sulfonic acid {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 556 (MH +); Y

Benzo [1,3] dioxol-5-carboxylic acid {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 488 (MH +).

BB In a manner similar to that described above in paragraph A, but replacing p-anisidine as intermediate starting material at a previous stage with 4-tert-butylaniline, the following compound was prepared:

4-tert-butyl-N- {1- [3- (4-tert-butyl-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 532 (MH +).

DC. In a manner similar to that described above in paragraph BB, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

N- {1- [3- (4-tert-Butyl-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-Nmethylbenzenesulfonamide; MS (ESI) 518 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-tert-butyl-phenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} methylamide; MS (ESI) 552 (MH +);

4-tert-butyl-N- {1- [3- (4-tert-butyl-phenyl) -4-oxo-3,

image128

4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 496 (MH +); Y

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-tert-butyl-phenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} methylamide; MS (ESI) 484 (MH +).

DD. In a manner similar to that described above in paragraph A, but replacing p-anisidine as intermediate starting material at a previous stage with m-anisidine, the following compound was prepared:

4-tert-butyl-N- {1- [3- (3-methoxyphenyl) -4-oxo-3,

4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide; MS (ESI) 506 (MH +).

USA In a manner similar to that described above in paragraph DD, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [3- (3-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 492 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (3-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 526 (MH +);

4-tert-butyl-N- {1- [3- (3-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 470 (MH +); Y

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (3-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 458 (MH +).

FF In a manner similar to that described above in paragraph A, but replacing p-anisidine as intermediate starting material at a previous stage with o-anisidine, the following compound was prepared:

4-tert-butyl-N- {1- [3- (2-methoxyphenyl) -4-oxo-3,

image129

4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide; MS (ESI) 506 (MH +).

GG In a manner similar to that described above in paragraph FF, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N- {1- [3- (2-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 492 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (2-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 526 (MH +);

4-tert-butyl-N- {1- [3- (2-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 470 (MH +); Y

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (2-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 458 (MH +).

H H. In a manner similar to that described above in paragraph A, but replacing p-anisidine as an intermediate starting material at a previous stage with

4-Trifluoromethoxyaniline, the following compound was prepared:

4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4trifluoromethoxyphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; MS (ESI) 560 (MH +).

II. In a manner similar to that described above in paragraph HH, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N-methyl-N- {1- [4-oxo-3- (4trifluoromethoxyphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; MS (ESI) 546 (MH +);

image130

Biphenyl 4-sulfonic acid methyl- {1- [4-oxo-3- (4-trifluoromethoxyphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} -amide; MS (ESI) 580 (MH +);

4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4trifluoromethoxyphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzamide; MS (ESI) 524 (MH +); Y

Benzo [1,3] dioxol-5-carboxylic acid methyl- {1- [4-oxo-3- (4-trifluoromethoxyphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} -amide; MS (ESI) 512 (MH +).

JJ. In a manner similar to that described above in paragraph A, but replacing p-anisidine as an intermediate starting material at a previous stage with

4-trifluoromethylaniline, the following compound was prepared:

4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4trifluoromethylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; MS (ESI) 544 (MH +).

KK In a manner similar to that described previously in paragraph JJ, but replacing the 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-isopropyl-N-methyl-N- {1- [4-oxo-3- (4trifluoromethylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; MS (ESI) 530 (MH +);

Biphenyl-4-sulfonic acid methyl- {1- [4-oxo-3- (4-trifluoromethylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} -amide; MS (ESI) 564 (MH +);

benzo [1,3] dioxol-5-carboxylic acid methyl- {1- [4-oxo-3- (4-trifluoromethylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} -amide; MS (ESI) 496 (MH +); Y

4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4trifluoromethylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzamide; MS (ESI) 508 (MH +).

image131

EXAMPLE 8 PREPARATION OF 4-TERC-BUTIL-N- {1- [3- (4-METOXIFENIL) -4-OXO3,4-DIHYDROQUINAZOLIN-2-IL] ETIL} -N-METHYLBENZAMIDE AND RELATED COMPOUNDS

A. To a suspension of 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one (50 mg, 0.16 mmol) with stirring in 2 ml of DCM, TEA (19 mg, 0.19 mmol) followed by the addition of pure 4-tert-butylbenzoyl chloride (31 mg, 0.16 mmol). The reaction was allowed to stir at room temperature for 2 h, then treated with trisamine (100 mg). The reaction was allowed to stand for 15 min. at room temperature, after which the resin was removed by filtration. The filtrate was concentrated in vacuo to yield the crude product. The crude residue was purified by flash chromatography (silica gel, 50% EtOAc / Hex) to yield the desired product as an off-white powder (73 mg, 97% yield). 1H NMR (CDCl3): ,1 8.15 (d, 1H), 7.55 (m, 1H), 7.39 (m, 4H), 7.25 (d, 1H), 7.16 (m, 2H ), 7.09 (m, 1H), 6.70 (m, 2H), 4.90 (c, 1H), 4.83 (s, 3H), 3.11 (s, 3H) 1.22 ( d, 3H), 1.09 (s, 9H); MS (ESI) 470 (MH +).

B. Similarly, but replacing 4terc-butylbenzoyl chloride with octanoyl chloride and 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 3 (2,4-dimethylphenyl) ) -2- (1-Methylaminoethyl) -3H-quinazolin-4-one, the following compound was prepared:

Nonanoic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 1H NMR (CDCl3):  8.32 (m, 1H), 7.80 (m, 2H), 7.55 (m, 1H), 7.19 (m, 2H), 7.06 (m, 1H ), 5.44 (c, 1H), 2.92 (m, 3H), 2.39 (m, 3H), 2.25 (m, 2H), 2.03 (m, 3H), 1.47 (m, 5H), 1.29 (m, 10H), 0.9 (m, 3H); MS (ESI) 448 (MH +).

image132

C. In a manner similar to that described in paragraph A above, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with the appropriate starting material, the following were prepared compounds:

4-tert-butyl-N- {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 1 H NMR (CDCl 3):  8.31 (d, 1 H), 7.80 (t, 1 H), 7.73 (m, 1 H), 7.64 (m, 1 H), 7.52 (t, 1 H ), 7.42 (m, 2H), 7.29 (m, 5H), 5.8 (c, 1H), 3.15 (s, 3H), 1.53 (d, 3H), 1.34 (s, 9H); MS (ESI) 458 (MH +);

4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 1 H NMR (CDCl 3): ,6 7.63 (m, 2H), 7.48 (m, 1H), 7.37 (m, 3H), 7.28 (m, 2H), 7.21 (m, 1H ), 7.04 (m, 2H), 5.46 (c, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 1.48 (d, 3H), 1.31 (s, 9H); MS (ESI) 500 (MH +);

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 1 H NMR (CDCl 3):  8.06 (m, 1H), 7.59 (m, 2H), 7.49 (m, 1H), 7.38 (m, 2H), 7.28 (m, 2H ), 7.21 (m, 1H), 7.04 (m, 2H), 5.45 (c, 1H), 3.83 (s, 3H), 3.08 (s, 3H), 2.49 (s, 3H), 1.48 (d, 3H), 1.31 (s, 9H); MS (ESI) 484 (MH +); Y

4-tert-Butyl-N-methyl-N- [1- (3-methyl-4-oxo-3,4dihydroquinazolin-2-yl) ethyl] benzamide; 1H NMR (CDCl3):  8.65 (d, 1H), 7.59 (width, 1H), 7.44 (m, 5H), 7.08 (t, 1H), 6.22 (c, 1H ), 3.02 (s, 3H), 3.01 (s, 3H), 1.54 (d, 3H), 1.33 (s, 9H); MS (ESI) 378 (MH +).

D. In a manner similar to that described above in paragraph A, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 3- (4-fluorophenyl) -2 (1 -methylaminoethyl) -3H-quinazolin-4-one and 4terc-butylbenzoyl chloride with the appropriate starting material, the following compounds were prepared:

image133

4-tert-butyl-N- {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 494 (MH +);

N- {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; MS (ESI) 480 (MH +); Y

Biphenyl-4-sulfonic acid {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 514 (MH +).

E. Similarly, but replacing 3- (4-methoxyphenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one with 3 (4-methoxyphenyl) -6-methyl-2- (1-methylaminoethyl) -3H-quinazolin-4one and replacing the 4-tert-butylbenzoyl chloride with the appropriate starting material, the following compounds were prepared:

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +);

4-isopropyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 506 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 540 (MH +);

N- {1- [3- (4-Methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 478 (MH +);

4-methoxy-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 494 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 472 (MH +);

image134

4-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 520 (MH +);

N- {1- [3- (4-Methoxyphenyl) -6-methyl-4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methyl-4trifluoromethylbenzenesulfonamide; MS (ESI) 532 (MH +); Y

2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 566 (MH +).

EXAMPLE 9

PREPARATION OF N- [1- (3-BIFENIL-4-IL-4-OXO-3,4

DIHYDROQUINAZOLIN-2-IL) ETIL] -4-TERC-BUTIL-N

Methylbenzenesulphonamide and related compounds

A. An oven-dried flask loaded with N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzenesulfonamide (103 mg, 0.19 mmol) was diluted with 2 ml of a solution purged with DME / H2O nitrogen (1: 1). The resulting reaction mixture was then treated with K2CO3 (78.8 mg, 0.57 mmol) and phenylboronic acid (46.3 mg, 0.38 mmol) at room temperature under a nitrogen atmosphere. In a different oven-dried vial containing triphenylphosphine (43.9 mg, 0.17 mmol) and Pd2dba3: CHCI3 (17 mg, 0.019 mmol) 1 ml of the solution purged with DME / H2O nitrogen (1: one). The contents of the vial were shaken until the Pd (0) had completely dissolved. The pre-mixed palladium solution was then added to the reaction mixture and heated at 70 ° C under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was then taken up in EtOAc and filtered through a bed of silica. The filtrate was concentrated in vacuo to yield a crude residue that was purified by chromatography (silica gel, 0-75% EtOAC: Hex) to yield the desired product as a white solid (74 mg, 71% yield). . 1H NMR (CDCl3):  8.26 (d, 1H), 7.88 (d, 1H), 7.76 (d, 1H), 7.67 (m, 4H), 7.45 (m, 7H ), 7.23 (m, 3H), 4.99 (c, 1H), 3.20 (s, 3H), 1.33 (d, 3H), 1.16 (s, 9H); MS (ESI) 552 (MH +).

image135

B. Similarly, but replacing phenylboronic acid with the appropriate starting material, the following compounds were prepared:

4-tert-Butyl-N-methyl-N- {1- [4-oxo-3- (4-thiophen-2-ylphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; 1H NMR (CDCl3):  8.23 (m, 1H), 7.79 (m, 1H), 7.67 (m, 3H), 7.47 (m, 7H), 7.39 (m, 2H ), 7.08 (m, 1H), 4.90 (c, 1H), 3.12 (s, 3H), 3.12 (s, 3H), 1.29 (d, 3H), 1.20 (s, 9H); MS (ESI) 558 (MH +);

4-tert-butyl-N- {1- [3- (3'-methoxy-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1H NMR (CDCl3): ,2 8.25 (d, 1H), 7.87 (m, 1H), 7.75 (m, 1H), 7.65 (m, 2h), 7.52 (m, 2H ), 7.41 (m, 3H), 7.25 (m, 5H), 6.95 (m, 1H), 4.98 (c, 1H), 3.89 (s, 3H), 3.20 (s, 3H), 1.31 (d, 3H), 1.16 (s, 9H); MS (ESI) 582 (MH +);

4-tert-butyl-N- {1- [3- (3'-chloro-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1 H NMR (CDCl 3): ,2 8.25 (d, 1 H), 7.86 (m, 1 H), 7.73 (m, 1 H), 7.66 (m, 3 H), 7.55 (m, 1 H ), 7.52 (d, 2H), 7.46 (t, 1H), 7.40 (m, 3H), 7.26 (m, 3H), 4.97 (c, 1H), 3.16 (d, 3H), 1.31 (d, 3H), 1.17 (s, 9H); MS (ESI) 587 (MH +);

4-tert-butyl-N-methyl-N- {1- [3- (2'-methyl-biphenyl-4-yl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; MS (ESI) 566 (MH +);

4-tert-butyl-N-methyl-N- {1- [3- (3'-methyl-biphenyl-4-yl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; MS (ESI) 566 (MH +);

4-tert-butyl-N-methyl-N- {1- [3- (4'-methyl-biphenyl-4-yl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; MS (ESI) 566 (MH +);

image136

4-tert-butyl-N- {1- [3- (2'-chloro-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 586 (MH +);

4-tert-butyl-N- {1- [3- (4'-chloro-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 586 (MH +);

4-tert-butyl-N- {1- [3- (2'-methoxy-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 582 (MH +);

4-tert-butyl-N- {1- [3- (4'-methoxy-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 582 (MH +);

4 '- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -biphenyl-4-carboxylic acid; MS (ESI) 596 (MH +);

4-tert-butyl-N- {1- [3- (4'-cyano-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 577 (MH +);

4-tert-Butyl-N-methyl-N- {1- [4-oxo-3- (4-thiophen-3-ylphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; MS (ESI) 558 (MH +);

4 '- (2- {1 - [(4-tert-butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -biphenyl-3-carboxylic acid methyl ester; MS (ESI) 610 (MH +);

4 '- (2- {1 - [(4-tert-butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3yl) -biphenyl-4-carboxylic acid methyl ester; MS (ESI) 610 (MH +);

4 '- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -biphenyl-3-carboxylic acid; MS (ESI) 596 (MH +); Y

C. The following three compounds were prepared by a modification of the procedure of paragraph B, as described in Wolfe et al., J. Org. Chem. (2000), Vol. 65, p. 1158-1174.

image137

4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-piperidin-1-ylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; 1 H NMR (CDCl 3):  8.21 (m, 1H), 7.60 (m, 2H), 7.51 (d, 2H), 7.39 (m, 2H), 7.20 (m, 2H ), 7.13 (m, 1H), 7.00 (m, 2H), 5.01 (c, 1H), 3.29 (m, 4H), 3.23 (s, 3H), 1.74 (m, 4H), 1.30 (d, 3H), 1.26 (m, 2H), 1.14 (s, 9H); MS (ESI) 559 (MH +);

4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-pyrrolidin-1-phenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; MS (ESI) 545 (MH +); Y

4-tert-butyl-N-methyl-N- {1- [3- (4-morpholin-4-ylphenyl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; 1H NMR (CDCl3):  8.22 (d, 1H), 7.62 (m, 1H), 7.52 (d, 2H), 7.424 (m, 2H), 7.30 (d, 1H), t.22 (d, 2H), 7.14 (d, 1H), 7.03 (m, 2H), 5.01 (c, 1H), 3.90 (s, 3H), 3.28 (m , 3H), 3.21 (s, 3H), 1.31 (d, 3H), 1.14 (s, 9H); MS (ESI) 561 (MH +).

D. In a manner similar to that described above in paragraph A, but replacing phenylboronic acid with thiophene-2-boronic acid and N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin- 2-yl] ethyl} -4-tert-butyl-Nmethylbenzenesulfonamide with N- [1- (6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4- tert-butyl-N-methylbenzenesulfonamide, the following compound was prepared:

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-thiophene-2yl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1H NMR (CDCl3):  8.34 (d, 1H), 7.71 (m, 2H), 7.5 (d, 2H), 7.46 (m, 3H), 7.35 (d, 1H ), 7.22 (m, 4H) 7.05 (d, 1H), 4.92 (c, 1H), 3.17 (s, 3H), 2.48 (s, 3H), 1.29 ( d, 3H), 1.19 (s, 9H); MS (ESI) 570 (MH +).

E. In a manner similar to that described above in paragraph D, but replacing thiophene-2-boronic acid with the appropriate starting material, the following compounds were prepared:

image138

4- [2 - {1 - [(4- tert -butyl-benzenesulfonyl) methylamino] ethyl} -3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-6-yl] benzoic acid; 1H NMR (CDCl3): ,4 8.48 (d, 1H), 8.21 (m, 2H), 7.92 (m, 1H), 7.74 (d, 2H), 7.54 (d, 2H ), 7.46 (m, 4H), 7.36 (m, 1H), 7.24 (m, 1H), 7.08 (m, 1H), 4.96 (c, 1H), 3.21 (s, 3H), 2.49 (s, 3H), 1.32 (d, 3H), 1.15 (s, 9H); MS (ESI) 610 (MH +);

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-m-tolyl3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1H NMR (CDCl3): ,4 8.41 (m, 1H), 7.87 (m, 2H), 7.53 (m, 2H), 7.45 (m, 3H), 7.37 (m, 3H ), 7.23 (m, 3H), 7.07 (m, 1H), 4.96 (c, 1H), 3.21 (s, 3H), 2.49 (s, 3H), 2.43 (s, 3H), 1.32 (d, 3H), 1.15 (s, 9H); MS (ESI) 580 (MH +);

4-tert-butyl-N- {1- [6- (3-chlorophenyl) -3- (4-methoxyphenyl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1H NMR (CDCl3): ,3 8.39 (d, 1H), 7.84 (m, 1H), 7.61 (m, 1H), 7.53 (m, 2H), 7.47 (m, 3H ), 7.40 (d, 2H), 7.37 (m, 2H), 7.24 (m, 2H), 7.07 (m, 1H), 4.95 (c, 1H), 3.20 (s, 3H), 2.49 (s, 3H), 1.31 (d, 3H), 1.15 (s, 9H); MS (ESI) 601 (MH +);

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-thiophene-3yl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1 H NMR (CDCl 3):  8.33 (d, 1 H), 7.71 (m, 1 H), 7.50 (m, 3 H), 7.44 (m, 3 H), 7.35 (m, 1 H ), 7.22 (m, 4H), 7.04 (m, 1H), 4.91 (c, 1H), 3.17 (s, 3H), 2.48 (s, 3H), 1.29 (d, 3H), 1.17 (s, 9H); MS (ESI) 570 (MH +);

4-tert-butyl-N-methyl-N- [1- (4-oxo-6-phenyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 566 (MH +);

image139

4-tert-Butyl-N-methyl-N- [1- (4-oxo-6-o-tolyl-3-p-tolyl3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 580 (MH +);

4-tert-butyl-N-methyl-N- [1- (4-oxo-3,6-di-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 580 (MH +);

4-tert-butyl-N- {1- [6- (2-chlorophenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 600 (MH +);

4-tert-butyl-N- {1- [6- (4-chlorophenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 600 (MH +);

4-tert-butyl-N- {1- [6- (2-methoxyphenyl) -4-oxo-3-p-tolyl3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 596 (MH +);

4-tert-butyl-N- {1- [6- (3-methoxyphenyl) -4-oxo-3-p-tolyl3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 596 (MH +);

4-tert-butyl-N- {1- [6- (4-methoxyphenyl) -4-oxo-3-p-tolyl3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 596 (MH +);

3- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl) benzoic acid methyl ester; MS (ESI) 624 (MH +);

4- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl) -benzoic acid methyl ester; MS (ESI) 624 (MH +);

3- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl) benzoic acid; MS (ESI) 610 (MH +); Y

4-tert-butyl-N- {1- [6- (4-cyanophenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 591 (MH +).

image140

F. The following three compounds were prepared by a modification of the procedure of paragraph D, as described in Wolfe et al., J. Org. Chem. (2000), Vol. 65, p. 1158-1174.

4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-pyrrolidin-1-yl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1 H NMR (CDCl 3):  7.51 (d, 2H), 7.43 (m, 2H), 7.33 (d, 1H), 7.24 (m, 3H), 7.17 (m, 1H ), 7.05 (d, 1H), 6.93 (d, 1H), 4.92 (c, 1H), 3.35 (m, 4H), 3.12 (s, 3H), 2.47 (s, 3H), 2.04 (m, 4H), 1.28 (d, 3H), 1.18 (s, 9H); MS (ESI) 559 (MH +);

4-tert-butyl-N-methyl-N- [1- (6-morpholin-4-yl-4-oxo-3-ptolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 575 (MH +); Y

4-tert-butyl-N-methyl-N- [1- (4-oxo-6-piperidin-1-yl-3-ptolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 573 (MH +).

EXAMPLE 10 PREPARATION OF 4-TERC-BUTIL-N- {1- [3- (4-HIDROXIFENIL) -4-OXO3,4-DIHYDROCHINAZOLIN-2-IL] ETIL} -N-METHYLBENHENOSULFONAMIDE AND RELATED COMPOUNDS

A. To a suspension of 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide (0.5 g, 1 , 07 mmol) with stirring in 15 ml of DCM, boron tribromide (5 ml, 5 mmol 1 M in DCM) was added. The reaction was allowed to stir at room temperature for 15 min., After which the TLC analysis indicated that the starting material had been completely consumed. The reaction was stopped with 20 ml of brine and the resulting mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with CHCl3 (2 x 25 ml). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to yield a crude residue that was purified by chromatography (silica gel, 0-75% EtOAc: Hex), yielding the desired product as of a white solid (0.735 g, 95%). 1H NMR (CDCl3):  8.26 (d, 1H), 7.67 (t, 1H), 7.51 (d, 2H), 7.45 (t, 1H), 7.36 (m, 2H ), 7.26 (d, 2H), 6.98 (m, 1H), 6.90 (m, 2H), 5.00 (c, 1H), 3.19 (s, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI) 492 (MH +).

image141

B. Similarly, but replacing 4-tert-butylN- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -N-methylbenzenesulfonamide with 4-tert -butyl-N- [1- (6-methoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -Nmethylbenzenesulfonamide, the following compound was prepared:

4-tert-butyl-N- [1- (6-hydroxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; 1H NMR (CDCl3):  7.82 (d, 1H), 7.49 (m, 3H), 7.42 (d, 1H), 7.36 (d, 1H), 7.24 (m, 4H ), 7.06 (d, 1H), 6.21 (s, 1H), 4.94 (c, 1H), 3.13 (s, 3H), 2.48 (s, 3H), 1.27 (d, 3H), 1.18 (s, 9H); MS (ESI) 506 (MH +).

C. In a manner described above in paragraph A, 4-tert-butyl-N- {1- [5-hydroxy-3- (4-hydroxyphenyl) -4oxo-3,4-dihydroquinazolin-2-yl was prepared ] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 508 (MH +); from 4terc-butyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide, which was prepared as prepared described above in Example 7.

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EXAMPLE 11 PREPARATION OF N- {1- [3- (4-BENCILOXIFENIL) -4-OXO-3,4DIHYDROQUINAZOLIN-2-IL] ETIL} -4-TERC-BUTIL-NMETILBENCENOSULFONAMIDE AND RELATED COMPOUNDS

A. To a solution of 4-tert-butyl-N- {1- [3- (4-hydroxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide (50 mg, 0.11 mmol ) in anhydrous THF (2 ml) triphenylphosphine (0.115 mg, 0.44 mmol), diisopropyl azodicarboxylate (88.9 mg, 0.44 mmol), and benzyl alcohol (48.5 mg, 0.44 mmol) were added to 0 ° C The mixture was stirred for 1 h at this temperature and then allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, and the crude residue was purified by chromatography (silica gel, 050% EtOAc: Hex) to yield the desired product as a white solid (48 mg, 80%). 1H NMR (CDCl3):  8.22 (d, 1H), 7.64 (m, 1H), 7.49 (m, 5H), 7.42 (m, 3H), 7.34 (m, 2H ), 7.24 (m, 3H), 7.10 (m, 2H), 5.15 (s, 2H), 4.99 (c, 1H), 3.19 (s, 3H), 1.30 (d, 3H), 1.16 (s, 9H); MS (ESI) 582 (MH +).

B. Similarly, but replacing the benzyl alcohol with the appropriate starting material, the following compounds were prepared:

4-tert-butyl-N- {1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 1H NMR (CDCl3):  8.22 (d, 1H), 7.64 (t, 1H), 7.43 (m, 2H), 7.33 (d, 1H), 7.23 (m, 2H ), 7.15 (d, 1H), 7.05 (dd, 2H), 4.98 (c, 1H), 4.13 (c, 2H), 3.19 (s, 3H), 1.47 (t, 3H), 1.29 (d, 3H), 1.16 (s, 9H); MS (ESI) 520 (MH +);

4-tert-Butyl-N-methyl-N- (1- {4-oxo-3- [4- (2-piperidin-1-ylethoxy) -phenyl] -3,4-dihydroquinazolin-2-yl} ethyl) benzenesulfonamide; 1H NMR (CDCl3):  8.23 (d, 1H), 7.67 (m, 2H), 7.46 (m, 4H), 7.30 (d, 2H), 7.15 (m, 2H ), 7.06 (m, 1H), 5.00 (c, 1H), 4.50 (m, 2H), 3.76 (m, 2H), 3.54 (m, 2H), 3.07 (s, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI) 603 (MH +);

image143

4-tert-butyl-N-methyl-N- (1- {3- [4- (2-morpholin-4-yl-ethoxy) phenyl] -4-oxo-3,4-dihydroquinazolin-2-yl} ethyl) benzenesulfonamide ; 1H NMR (CDCl3):  8.25 (d, 1H), 7.69 (t, 1H), 7.53 (d, 2H), 7.46 (m, 3H), 7.31 (d, 2H ), 7.15 (m, 2H), 7.07 (m, 1H), 5.00 (c, 1H), 4.52 (m, 2H), 4.01 (m, 4H) 3.71 ( m, 2H), 3.58 (m, 2H), 3.09 (m, 2H), 3.03 (m, 2H), 2.72 (s, 3H), 1.28 (d, 3H), 1.21 (s, 9H); MS (ESI) 605 (MH +);

[4- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) phenoxy] acetic acid ethyl ester; 1 H NMR (CDCl 3):  8.22 (d, 1 H, 7.65 (t, 1 H), 7.50 (d, 3 H), 7.44 (t, 1 H), 7.36 (d, 1 H) , 7.27 (s, 2H), 7.16 (d, 1H), 7.10 (s, 2H), 4.94 (c, 1H), 4.71 (s, 2H), 4.31 ( c, 2H), 3.17 (s, 3H), 1.33 (t, 3H), 1.26 (d, 2H), 1.18 (s, 9H); MS (ESI) 578 (MH +);

4-tert-butyl-N- (1- {3- [4- (2-methoxyethoxy) phenyl] -4-oxo-3,4-dihydroquinazolin-2-yl} ethyl) -N-methylbenzenesulfonamide; 1H NMR (CDCl3):  8.22 (d, 1H), 7.64 (t, 1H), 7.45 (m, 4H), 7.33 (d, 1h), 7.21 (m, 3H ), 7.09 (s, 2H), 4.97 (c, 1H), 4.22 (t, 2H), 3.81 (t, 2H), 3.49 (s, 3H), 3.19 (d, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI) 550 (MH +);

4-tert-butyl-N- {1- [3- (4-n-butoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide;

4-tert-butyl-N- {1- [3- (4-isopropoxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 534 (MH +); Y

4-tert-butyl-N- {1- [3- (4-isobutoxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 548 (MH +).

image144

C. In a manner similar to that described above in paragraph A, but replacing 4-tert-butyl-N- {1- [3- (4-hydroxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl } -N-methylbenzenesulfonamide with 4-tert-butyl-N- [1- (6-hydroxy-4oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide, the following compounds were prepared:

N- [1- (6-Benzyloxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin2-yl) ethyl] -4-tert-butyl-N-methylbenzenesulfonamide; 1H NMR (CDCl3): ,6 7.67 (d, 1H), 7.50 (m, 2H), 7.44 (m, 4H), 7.39 (m, 2H), 7.34 (m, 2H ), 7.30 (m, 2H), 7.24 (m, 1H), 7.05 (m, 1H), 5.13 (s, 2H), 4.93 (c, 1H), 3.14 (s, 3H), 2.48 (s, 3H), 1.28 (d, 3H), 1.18 (s, 9H); MS (ESI) 596 (MH +).

D. In a manner similar to that described above in paragraph C, but replacing the benzyl alcohol with the appropriate starting material, the following compounds were prepared:

4-tert-butyl-N- [1- (6-isobutoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; 1H NMR (CDCl3): ,5 7.54 (d, 1H), 7.50 (m, 2H), 7.45 (m, 1H), 7.43 (m, 1H), 7.33 (m, 1H ), 7.24 (m, 4H), 7.04 (m, 1H), 4.93 (c, 1H), 3.79 (d, 2H), 3.15 (s, 3H), 2.48 (s, 3H), 1.28 (d, 3H), 1.17 (s, 9H); MS (ESI) 562 (MH +);

N- [1- (6-Butoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzenesulfonamide; 1H NMR (CDCl3):  7.5 (m, 3H), 7.46 (m, 1H), 7.40 (m, 1H), 7.34 (m, 3H), 7.26 (m, 2H ), 7.05 (m, 1H), 4.94 (c, 1H), 4.69 (s, 2H), 4.27 (c, 2H), 3.13 (s, 3H), 2.48 (s, 3H), 1.31 (t, 3H), 1.27 (d, 3H), 1.19 (s, 9H); MS (ESI) 562 (MH +);

(2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yloxy) acetic acid ethyl ester; 1H NMR (CDCl3): ,5 7.56 (d, 1H), 7.50 (m, 2H), 7.44 (m, 2H), 7.33 (m, 1H), 7.24 (m, 4H ), 7.05 (m, 1H), 4.93 (c, 1H), 4.03 (t, 2H), 3.15 (s, 3H), 2.48 (s, 3H), 1.79 (m, 2H), 1.5 (m, 2H), 1.28 (d, 1H), 1.18 (s, 9H), 0.98 (t, 3H); MS (ESI) 592 (MH +);

image145

4-tert-butyl-N- [1- (6-ethoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; MS (ESI) 534 (MH +); Y

4-tert-butyl-N- [1- (6-isopropoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; MS (ESI) 548 (MH +).

E. In a manner similar to that described in paragraph A, but replacing the intermediate starting material, 4-tert-butylbenzenesulfonyl chloride, at a previous stage, with an appropriate intermediate starting material, the following compounds were prepared:

N- {1- [3- (4-Benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; MS (ESI) 568 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 602 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 534 (MH +); Y

N- {1- [3- (4-Benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-tert-butyl-N-methylbenzamide; MS (ESI) 546 (MH +).

EXAMPLE 12 PREPARATION OF 3- (4-BROMOFENIL) -2- (1-METHYLAMINE) -3HQUINAZOLIN-4-ONA AND RELATED COMPOUNDS

A. The title compound was prepared from 3- (4-bromophenyl) -2- (1-chloroethyl) -3H-quinazolin-4-one (prepared above in Example 3) and methylamine under conditions similar to those described in Example 5 above, MS (ESI) 358 (MH +).

image146

B. In a manner similar to that described above in Example 7, 3- (4-bromophenyl) -2- (1-methylaminoethyl) -3Hquinazolin-4-one was condensed with benzylsulfonyl chloride to produce N- {1- [ 3- (4-bromophenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 498 (MH +).

C. In a manner similar to that described above in paragraph B, but replacing the benzyl sulfonyl chloride with the appropriate starting material, the following compounds were prepared:

N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; MS (ESI) 528 (MH +);

N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 512 (MH +);

N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -4-chloro-N-methylbenzenesulfonamide; MS (ESI) 533 (MH +);

N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzenesulfonamide; MS (ESI) 554 (MH +);

N- {1- [3- (4-Bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; MS (ESI) 540 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 574 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 506 (MH +);

image147

N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 566 (MH +); Y

N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzamide; MS (ESI) 518 (MH +).

EXAMPLE 13 PREPARATION OF 2- (1-METHYLAMINE) -3-PHENYL-3H-QUINAZOLIN-4ONA AND RELATED COMPOUNDS

A. In a manner similar to that described above in Example 3 and Example 5, but replacing the p-anisidine with aniline, the title compound was prepared; MS (ESI) 280 (MH +).

B. In a manner similar to that described above, but replacing p-anisidine with 4-fluoroaniline, the following compound was prepared:

3- (4-fluorophenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4one; MS (ESI) 298 (MH +).

C. In a manner similar to that described above in Example 7, 2- (1-methylaminoethyl) -3-phenyl-3H-quinazolin-4one, prepared as described above in paragraph A, was condensed with benzenesulfonyl chloride to produce N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 420 (MH +).

D. In a manner similar to that described above, but replacing the benzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-methoxy-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 450 (MH +);

4, N-dimethyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 434 (MH +);

image148

4-Chloro-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 454 (MH +);

4-tert-butyl-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 476 (MH +);

4-isopropyl-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; MS (ESI) 462 (MH +);

Biphenyl-4-sulfonic acid methyl- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] amide; MS (ESI) 496 (MH +);

4-tert-butyl-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzamide; MS (ESI) 440 (MH +);

benzo [1,3] dioxol-5-carboxylic acid methyl- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2yl) ethyl] amide; MS (ESI) 428 (MH +); Y

N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-trifluoromethylbenzenesulfonamide; MS (ESI) 488 (MH +).

E. In a manner similar to that described above in paragraph A, but replacing p-anisidine with 4-chloroaniline, the following compound was prepared:

3- (4-chlorophenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4one; MS (ESI) 314 (MH +).

F. In a manner similar to that described above in Example 7, 3- (4-chlorophenyl) -2- (1-methylaminoethyl) -3Hquinazolin-4-one was condensed with o-anisoyl chloride to produce N- {1 - [3- (4-Chlorophenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -2-methoxy-N-methylbenzamide; MS (ESI) 448 (MH +).

G. In a manner similar to that described above in paragraph F, but replacing o-anisoyl chloride with the appropriate starting material, the following compounds were prepared:

image149

N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -3-methoxy-N-methylbenzamide; MS (ESI) 448 (MH +);

N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzamide; MS (ESI) 448 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 462 (MH +);

N- {1- [3- (4-Chlorophenyl) -4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-terephthalamic acid methyl ester; MS (ESI) 476 (MH +);

4-tert-butyl-N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 474 (MH +);

4-tert-butyl-N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 510 (MH +);

N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; MS (ESI) 484 (MH +); Y

Nonanoic acid {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 454 (MH +).

H. In a manner similar to that described above in Example 3, Example 5 and Example 7, but replacing p-anisidine with 4-aminobenzonitrile, the following compound was prepared:

4-tert-butyl-N- {1- [3- (4-cyanophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 501 (MH +).

I. 4-tert-Butyl-N- {1- [3- (4-cyanophenyl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -Nmethylbenzenesulfonamide, prepared as described above in the paragraph, was hydrolyzed H, with HCl concentrated at reflux to produce 4- (2- {1 - [(4-tert-butyl-benzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -benzoic acid; MS (ESI) 520 (MH +).

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J. In a manner similar to that described above in Example 3 and Example 5, but replacing p-anisidine with 3,5-dimethylaniline, the following compound was prepared:

3- (3,5-dimethylphenyl) -2- (1-methylaminoethyl) -3H-quinazolin4-one; MS (ESI) 308 (MH +).

K. In a manner similar to that described above in paragraph J, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

4-tert-butyl-N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 468 (MH +);

Benzo [1,3] dioxol-5-carboxylic acid {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 456 (MH +);

4-tert-butyl-N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 504 (MH +);

N- {1- [3- (3,5-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; MS (ESI) 490 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; MS (ESI) 524 (MH +);

N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; MS (ESI) 462 (MH +);

N- {1- [3- (3,5-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; MS (ESI) 478 (MH +);

N- {1- [3- (3,5-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 448 (MH +);

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4-Chloro-N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 482 (MH +); Y

N- {1- [3- (3,5-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 516 (MH +).

L. In a manner similar to that described above in Example 3 and Example 5, but replacing p-anisidine with 4-dimethylaminoaniline, the following compound was prepared:

3- (4-dimethylamino-phenyl) -2- (1-methylaminoethyl) -3Hquinazolin-4-one; MS (ESI) 323 (MH +).

M. In a manner similar to that described above in Example 7, the 3- (4-dimethylamino-phenyl) -2- (1-methylaminoethyl) -3H-quinazolin-4-one, prepared above in paragraph L, was condensed with chloride of 4-tert-butylbenzenesulfonyl to produce 4-tert-butyl-N- {1- [3- (4-dimethylamino-phenyl) -4oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; MS (ESI) 519 (MH +).

N. In a manner similar to that described above in paragraph M, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

N- {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -4-isopropyl-Nmethylbenzenesulfonamide; MS (ESI) 505 (MH +);

Biphenyl-4-sulfonic acid {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 539 (MH +);

Venzo [1,3] dioxol-5-carboxylic acid {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; MS (ESI) 471 (MH +); Y

4-tert-butyl-N- {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; MS (ESI) 483 (MH +).

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EXAMPLE 14

PREPARATION OF 4-TERC-BUTIL-N- [3- (2,4-DIMETHYLPHENYL) -4-OXO

3,4-DIHIDROQUINAZOLIN-2-ILMETIL] -N-METHYLBENZENOSULPHONAMIDE AND

RELATED COMPOUNDS

In a manner similar to that described above in Example 3 and Example 5, but with the appropriate starting materials, the following compound was prepared:

3- (2,4-dimethylphenyl) -2-methylamino-methyl-3H-quinazolin-4one; MS (ESI) 294 (MH +).

B. In a manner similar to that described above in Example 7, 3- (2,4-dimethylphenyl) -2-methylaminomethyl-3H-quinazolin-4-one was condensed with 4-tert-butylbenzenesulfonyl chloride to produce the title compound, MS (ESI) 490 (MH +).

C. In a manner similar to that described above, but replacing 4-tert-butylbenzenesulfonyl chloride with the appropriate starting material, the following compounds were prepared:

Benzo [1,3] dioxol-5-carboxylic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 442 (MH +);

4-tert-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -N-methylbenzamide; MS (ESI) 454 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methoxy-N-methylbenzenesulfonamide; MS (ESI) 464 (MH +);

4-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 468 (MH +);

Octane-1-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 470 (MH +);

image153

Quinoline-8-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 485 (MH +);

Naphthalene-1-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 484 (MH +);

2-Naphthalen-1-yl-ethanesulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 512 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2, N-dimethylbenzenesulfonamide; MS (ESI) 448 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] -3, N-dimethylbenzenesulfonamide; MS (ESI) 448 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4, N-dimethylbenzenesulfonamide; MS (ESI) 448 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-C-phenyl-methanesulfonamide; MS (ESI) 448 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-3-trifluoromethylbenzenesulfonamide; MS (ESI) 502 (MH +);

N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-4-trifluoromethoxy-benzenesulfonamide; MS (ESI) 518 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,5, N-trimethylbenzenesulfonamide; MS (ESI) 462 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -3,4-dimethoxy-N-methylbenzenesulfonamide; MS (ESI) 494 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,4,6, N-tetramethylbenzenesulfonamide; MS (ESI) 476 (MH +);

image154

2-Phenyl-ethenesulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 460 (MH +);

2,2,5,6,8-pentamethyl-chroman-7sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 560 (MH +);

Thiophene-2-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 440 (MH +);

C- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-yl) -N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl ] -N-methylmethanesulfonamide; MS (ESI) 508 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -3,4-difluoro-N-methylbenzenesulfonamide; MS (ESI) 470 (MH +);

3-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -2, N-dimethylbenzenesulfonamide; MS (ESI) 482 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -5-fluoro-2, N-dimethylbenzenesulfonamide; MS (ESI) 466 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-4-trifluoromethylbenzenesulfonamide; MS (ESI) 502 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] -3-fluoro-N-methylbenzenesulfonamide; MS (ESI) 452 (MH +);

2,4,6-trichloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 536 (MH +);

3-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -4-fluoro-Nmethylbenzenesulfonamide; MS (ESI) 486 (MH +);

image155

2-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 468 (MH +);

5-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -2-methoxy-Nmethylbenzenesulfonamide; MS (ESI) 498 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,5-dimethoxy-N-methylbenzenesulfonamide; MS (ESI) 494 (MH +);

N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,3,4-trifluoro-N-methylbenzenesulfonamide; MS (ESI) 488 (MH +);

3-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 468 (MH +);

Biphenyl-4-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 510 (MH +);

4-cyano-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 459 (MH +);

4-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 490 (MH +);

N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4- (1,1-dimethyl-propyl) -N-methylbenzenesulfonamide; MS (ESI) 504 (MH +);

N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-isopropyl-N-methylbenzenesulfonamide; MS (ESI) 476 (MH +);

4-Butoxy-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; MS (ESI) 506 (MH +);

image156

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -3-methoxy-N-methylbenzenesulfonamide; MS (ESI) 464 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2-methoxy-4, N-dimethylbenzenesulfonamide; MS (ESI) 478 (MH +);

4-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-ylmethyl] -2,5, N-trimethylbenzenesulfonamide; MS (ESI) 496 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methylmethanesulfonamide; MS (ESI) 372 (MH +);

Butane-1-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 414 (MH +);

3-Chloropropane-1-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; MS (ESI) 434 (MH +);

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-3,5-bis-trifluoromethylbenzenesulfonamide; MS (ESI) 570 (MH +); Y

N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-4-nitrobenzenesulfonamide; MS (ESI) 479 (MH +).

EXAMPLE 15

ENERGY TRANSFER TEST BY RESONANCE OF

FLUORESCENCE RESOLVED IN TIME (TR-FRET)

The FRET assay was performed by incubating 8 nM GST-FXR-LBD (comprising phase-fused glutathione-S-transferase with the FXR LBD (amino acids 244-471 of human FXR), anti-GST antibody labeled with 8 nM europium (Wallac / PE Life Sciences Cat. No. AD0064), 16 nM biotin-SRC-1 peptide [5'-biotinCPSSHSSLTERHKILHRLLQEGSPS-CONH2], APC-SA 20 nM [streptavidin conjugated to allophycocyanin] (Wallac / PE Life Sciences, car no. AD0059A) in 20 mM FRET assay buffer (KH2PO4 / K2HPO4 (pH 7.3), 150 mM NaCl, 2 mM CHAPS, 2 mM EDTA, 1 mM DTT) in the presence of the test compound or compounds for 2-4 hours at room temperature The data was collected using an LJL Analyst with readings at 615 nm and 665 nm after a delay of 65 y and an excitation wavelength of 330 nm.

image157

EXAMPLE 16

FXR CO-TRANSFECTION TEST

The basic co-transfection protocol for measuring FXR activity is as follows. CV-1 African green monkey kidney cells are seeded 24 hours before transfection to achieve a confluence of approximately 70-80 percent. Cells are transfected with CMX-hFXR, CMXRXR, Luc12 reporter (ECREx7-Tk-Luciferase), and a CMX--Galactosidase expression vector (see WO 00/76523). The transfection reagent used is DOTAP (Boehringer Mannheim). The cells are incubated with the DOTAP / DNA mixture for 5 hours, after which the cells are collected and seeded in 96-well or 384-well plates containing the appropriate concentration of test compound. The assay is allowed to continue for an additional 18-20 hours, after which the cells are lysed, with lysis buffer (1% triton X 100, 10% glycerol, 5 mM dithiothreitol, 1 mM EGTA, 25 mM tricine, pH 7.8) and luciferase activity is measured in the presence of luciferase assay buffer (0.73 mM ATP, 22.3 mM tricine, 0.11 mM EGTA, 0.55 mM luciferin, 0.15 mM coenzyme , 0.5 mM HEPES, 10 mM magnesium sulfate) in a conventional luminometric plate reader (PE Biosystems, NorthStar Reader).

image158

EXAMPLE 17

LIVE STUDIES

To evaluate the direct regulation of key target genes by the compounds of the invention, a single oral dose of the test compound was administered to animals and the tissues were collected at six or fifteen hours after the dose. Male C57BL / 6 mice (n = 8) were dosed by vehicle or compound oral probe. At six and fifteen hours after the dose, blood is drawn from the animals through the retro-orbital sinus for plasma collection. The animals are then sacrificed and tissues, such as the liver and intestinal mucosa, are collected and quickly frozen for further analysis. Plasma is analyzed for lipid parameters, such as levels of total cholesterol, HDL cholesterol and triglycerides. RNA is extracted from frozen tissues and can be analyzed by quantitative PCR in real time for the regulation of key target genes. To identify the specificity of the regulation of target genes by FXR, knockout mice (FXR - / -) and wild type C57BL / 6 controls can be used in this same protocol.

To compare the effects of the compounds on the plasma cholesterol and triglyceride levels, the compound is dosed to the animals for a week and the plasma lipid levels are monitored throughout the study. Male C57BL / 6 mice (n = 8) are dosed daily by vehicle or compound oral probe. Plasma samples are taken on day -1 (to classify the animals), on day 1, 3, and 7. Samples are collected three hours after the daily dose. On day 7 of the study, after plasma collection, animals are sacrificed and tissues, such as liver and intestinal mucosa, are collected and quickly frozen for further analysis. Plasma is analyzed for lipid parameters, such as levels of total cholesterol, HDL cholesterol and triglycerides. RNA is extracted from frozen tissues and can be analyzed by quantitative PCR in real time for the regulation of key target genes. To identify the specificity of the regulation of target genes by FXR, FXR knockout mice and wild type C57BL / 6 controls can be used in this same protocol.

image159

The evaluation of compounds to inhibit cholesterol absorption is done by measuring marked cholesterol in the stool. Male A129 mice (n = 7) are dosed daily by vehicle or compound oral probe for 7 days. On day 7 of the study, animals [14C] -cholesterol and [3H] -sitostanol are administered by oral probe. The animals are individually housed in wire racks for the next 24 hours to collect feces. Then the stool is dried and ground to a fine powder. The labeled cholesterol and sitostanol are extracted from the feces and the proportions of the two are counted in a liquid scintillation counter to assess the amount of cholesterol absorbed by the individual animal.

RESULTS OF EXAMPLES 15 AND 16

Both the FXR / ECREx7 co-transfection assay and the TR-FRET assay can be used to establish EC50 / IC50 values for potency and percent activity or inhibition. Efficacy defines the activity of a compound in relation to a high control (chenodeoxycholic acid, CDCA) or a low control (DMSO / vehicle). The dose response curves are generated from an 8-point curve with concentrations that differ in 1/2 LOG units. Each point represents the average of 4-well data from a 384-well plate. The curve for the data is generated using the following equation:

image160

Y = Lower + (upper - lower) / (1 + 10 ((logEC50-X) * pending))

The EC50 / IC50, therefore, is defined as the concentration at which an agonist or antagonist provokes a response that is in the center between the upper (maximum) and lower (initial) values. The EC50 / IC50 values represented are the averages of at least 3 independent experiments. The determination of the relative efficacy or% control for an agonist is by comparison with the maximum response achieved by chenodeoxycholic acid that is measured individually in each dose response experiment.

For the antagonist assay, CDCA is added to each well of a 384 well plate to elicit a response. The% inhibition for each antagonist is, therefore, a measure of the inhibition of CDCA activity. In this example, a 100% inhibition would indicate that CDCA activity has been reduced to baseline levels, defined as the activity of the assay in the presence of DMSO only.

Most of the compounds described in this document and tested showed activity in at least one of the previous tests (EC50 or IC50 less than 10 M). The majority showed activity below 1 M. For example, 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-thiophene-2-yl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide

image161

(Example 9) shows an EC50 of approximately 600 nM and a% efficacy of approximately 110% in the co-transfection assay; and 4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N

5-methylbenzenesulfonamide (Example 7) shows an EC50 of approximately 300 nM and a% efficacy of approximately 190% in the co-transfection assay.

image162

Claims (33)

1. A compound or salt thereof of formula (III): image 1 in which: n is an integer from 0 to 5; m is an integer from 0 to 4; t is an integer from 0 to 5; each R1a is independently selected from the group consisting of alkyl, hydroxy, alkoxy, alkoxyalkoxy, aralkoxy, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkoxy, heteroaryl, heterocyclyl, heterocyclyl (optionally) replaced with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, carboxy, cyano, and alkoxycarbonyl); R2 is hydrogen or alkyl; each R3 is independently selected from the group consisting of alkyl, alkoxy, halo, hydroxy, aralkoxy, alkoxycarbonylalkoxy, aryl (optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, alkoxy, carboxy, alkoxycarbonyl, cyano), heteroaryl and heterocyclyl; image2 R4 is hydrogen or alkyl; each R5a is independently selected from the group consisting of alkyl, alkoxy, halo, alkylcarbonyl, haloalkoxy, aryl, cyano, carboxy, alkoxycarbonyl, nitro, or two adjacent R5a groups form an aryl, heterocyclyl or heteroaryl; and R6 is hydrogen or alkyl.

2.

The compound or salt thereof of claim 1, wherein m is 0 or 1, n is 1 and each R1a is alkoxy.

3.

The compound or salt thereof of claim 2 selected from the group consisting of the following: N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] 4-methylbenzenesulfonamide; 4-tert-butyl-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzenesulfonamide; 4-methoxy-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] benzenesulfonamide; 4-chloro-N- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] benzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-Methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 4 - ({1- [3- (4-Methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -methyl-sulfamoyl) -benzoic acid; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin

image3 2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 4-methoxy-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-butyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (4-Methoxyphenyl) -5-methyl-4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 4-methoxy-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-butyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (4-Methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 4-methoxy-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [7-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [7-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 4-tert-butyl-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [6-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 2,4,6-trichloro-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3> 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (4-Methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; 4-methoxy-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-butyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 2,4,6-trichloro-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N- {1- [3- (3-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [3- (3-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (3-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N- {1- [3- (2-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-isopropyl-N- {1- [3- (2-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (2-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N- {1- [8-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [8-Chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [8-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N- {1- [3- (4-ethoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-isopropoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-isobutoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-n-butoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzenesulfonamide; 4-methoxy-N- {1- [3- (4-cyanophenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzenesulfonamide; and 4-tert-butyl-N- {1- [7-chloro-3- (4-methoxyphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide. image4 image5 image6

Four.

The compound or salt thereof of claim 1, wherein my is 0 or 1, n is 1, 2 or 3 and each R1a is selected from alkyl.

5.

The compound or salt thereof of claim 4 selected from the group consisting of the following: {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} acid methylamide quinoline-8-sulfonic; Naphthalene-1-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide;

image7 Naphthalene-2-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide, {1- [3- (2,4-dimethylphenyl) 2-Naphthalen-1-yl-ethanesulfonic acid -4-oxo-3,4-dihydroquinazolin-2-yl} ethyl} methylamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2, N-dimethylbenzenesulfonamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -3, N-dimethylbenzenesulfonamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-C-phenyl-methanesulfonamide; 4-acetyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-4-trifluoromethoxy-benzenesulfonamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2,5, N-trimethylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -3,4-dimethoxy-N-methylbenzenesulfonamide; N- [4 - ({1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -methyl-sulfamoyl) -phenyl] -acetamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2,4,6, N-tetramethylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -3,4-difluoro-N-methylbenzenesulfonamide; 3-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -2, N-dimethylbenzenesulfonamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -5-fluoro-2, N-dimethylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -3-fluoro-N-methylbenzenesulfonamide; 2,4,6-trichloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 3-chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -4-fluoro-Nmethylbenzenesulfonamide; 2-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 5-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -2-methoxy-Nmethylbenzenesulfonamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2,5-dimethoxy-N-methylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2,3,4-trifluoro-N-methylbenzenesulfonamide; 3-Chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-cyano-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4- (1,1-dimethyl-propyl) -N-methylbenzenesulfonamide; 4-butoxy-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2-methoxy-4, N-dimethylbenzenesulfonamide; 4-chloro-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -2,5, N-trimethylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-methanesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methylbenzenesulfonamide; 4-tert-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] benzenesulfonamide; N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methoxy-benzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; 4-tert-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-methoxy-N-methylbenzenesulfonamide; 4-chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -N-methylbenzenesulfonamide; Quinoline-8-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; Naphthalene-1-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2, N-dimethylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] -3, N-dimethylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4, N-dimethylbenzenesulfonamide; N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-4-trifluoromethoxy-benzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,5, N-trimethylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -3,4-dimethoxy-N-methylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,4,6, N-tetramethylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -3,4-difluoro-N-methylbenzenesulfonamide; 3-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -2, N-dimethylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -5-fluoro-2, N-dimethylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] -3-fluoro-N-methylbenzenesulfonamide; 2,4,6-trichloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -N-methylbenzenesulfonamide; 3-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -4-fluoro-N-methylbenzenesulfonamide; 2-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -N-methylbenzenesulfonamide; 5-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -2-methoxy-N-methylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,5-dimethoxy-N-methylbenzenesulfonamide; N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2,3,4-trifluoro-N-methylbenzenesulfonamide; 3-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methylmethyl] methylamide; 4-cyano-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -N-methylbenzenesulfonamide; 4-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -N-methylbenzenesulfonamide; N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4- (1,1-dimethyl-propyl) -N-methylbenzenesulfonamide; N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -4-isopropyl-N-methylbenzenesulfonamide; 4-butoxy-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -N-methylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -3-methoxy-N-methylbenzenesulfonamide; N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -2-methoxy-4, N-dimethylbenzenesulfonamide; 4-Chloro-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin2-ylmethyl] -2,5, N-trimethylbenzenesulfonamide; N- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] -N-methyl-4-nitro-benzenesulfonamide; 4-tert-butyl-N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1-3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid (1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (3,5- dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin- 2il] ethyl} -4-methoxy-N-methylbenzenesulfonamide; N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -N-methylbenzenesulfonamide; 4- chloro-N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3, 4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-tert-Butyl-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-tert-butyl-phenyl) - 4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; {1- [3- (4-tert-butyl-phenyl) -4-oxo-3,4-dihydroquinazolin-2il ] ethyl} biphenyl-4-sulfonic acid methylamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3, 4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-isopropyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3, 4-dihydroquinazolin-2-yl) ethyl] benzenesulf onamide; Biphenyl-4-sulfonic acid methyl- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2yl) ethyl] amide; 4-tert-butyl-N- [1- (6-methoxy-4-oxo-3-p-tolyl-3, 4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; 4-tert-butyl-N- [1- (6-hydroxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; N- [1- (6-Bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid [1- (6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2yl) ethyl] methylamide; N- [1- (6-Bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-isopropyl-N-methylbenzenesulfonamide; N- [1- (6-Benzyloxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzenesulfonamide; 4-tert-butyl-N- [1- (6-isobutoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; N- [1- (6-Butoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzenesulfonamide; (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yloxy) acetic acid ethyl ester; 4-tert-butyl-N- [1- (6-ethoxy-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-thiophene-3-yl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-6-phenyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-thiophene-2-yl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- {1- [3- (2'-methyl-biphenyl-4-yl) -4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; 4-tert-butyl-N-methyl-N- {1- [3- (3'-methyl-biphenyl-4-yl) -4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; 4-tert-butyl-N-methyl-N- {1- (4-oxo-6-o-tolyl-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-3,6-di-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-tert-butyl-N- {1- [6- (2-chlorophenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6- (4-chlorophenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6- (2-methoxyphenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6- (3-methoxyphenyl) -4-oxo-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6- (4-methoxyphenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 3- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl) benzoic acid methyl ester; 4- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl) -benzoic acid methyl ester; 3- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} 4-oxo-3-p-tolyl-3,4-dihydroquinazolin-6-yl) benzoic acid; 4-tert-butyl-N- {1- [6- (4-cyanophenyl) -4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- [1- (6-morpholin-4-yl-4-oxo-3-p-tolyl3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; and 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-m-tolyl-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-6-pyrrolidin-1-yl3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4- [2- {1 - [(4-tert-Butyl-benzenesulfonyl) methylamino] ethyl} -3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-6-yl] benzoic acid; 4-tert-butyl-N-methyl-N- [1- (4-oxo-6-piperidin-1-yl-3-p-tolyl3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-tert-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; and N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-methyl] benzenesulfonamide. image8 image9 image10 image11 image12 image13 image14

6.

The compound or salt thereof of claim 1, wherein m is 0 or 1, n is 1 and each R1a is independently selected from halo, haloalkoxy, and cyano.

7.

The compound or salt thereof of claim 6 selected from the group consisting of the following: 4-tert-butyl-N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl ] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide; N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-cyanophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-Bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4, N-dimethylbenzenesulfonamide; N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -4-chloro-N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-trifluoromethoxyphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; 4-isopropyl-N-methyl-N- {1- [4-oxo-3- (4-trifluoromethoxyphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; Biphenyl-4 acid methyl- (1- [4-oxo-3- (4-trifluoromethoxyphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} -amide

image15 sulfonic; 4-tert-butyl-N- {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-trifluoromethylphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; 4-isopropyl-N-methyl-N- {1- [4-oxo-3- (4-trifluoromethylphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; Biphenyl-4-sulfonic acid methyl- {1- [4-oxo-3- (4-trifluoromethylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} -amide; N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-Bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzenesulfonamide.

8.

The compound or salt thereof of claim 1, wherein m is 0 or 1, n is 0 or 1 and each R1a is selected from carboxy, dialkylamino, hydroxy, alkoxyalkoxy, alkoxycarbonylalkoxy, aralkoxy, and heterocyclylalkoxy.

9.

The compound or salt thereof of claim 8 selected from the group consisting of the following: 4- (2- {1 - [(4-tert-butyl-benzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin acid -3-yl) -benzoic; 4-tert-butyl-N- {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} methylamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-3-phenyl-3,

image16 4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-isopropyl-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; Biphenyl-4-sulfonic acid methyl- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] amide; N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-methoxy-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2yl) ethyl] benzenesulfonamide; 4, N-dimethyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-Chloro-N-methyl-N- [1- (4-oxo-3-phenyl-3,4-dihydroquinazolin-2yl) ethyl] benzenesulfonamide; N- {1- [3- (4-Benzyloxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzenesulfonamide; N- {1- [3- (4-Benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; Biphenyl-4-sulfonic acid {1- [3- (4-benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide; 4-tert-butyl-N- {1- [3- (4-hydroxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [5-hydroxy-3- (4-hydroxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-Butyl-N-methyl-N- (1- {4-oxo-3- [4- (2-piperidin-1-ylethoxy) phenyl] -3,4-dihydroquinazolin-2-yl} ethyl) benzenesulfonamide; 4-tert-butyl-N-methyl-N- (1- {3- [4- (2-morpholin-4-ylethoxy) phenyl] -4-oxo-3,4-dihydroquinazolin-2-yl} ethyl) benzenesulfonamide; [4- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) phenoxy] acetic acid ethyl ester; and 4-tert-butyl-N- (1- {3- [4- (2-methoxyethoxy) phenyl] -4-oxo-3,4-dihydroquinazolin-2-yl} ethyl) -N-methylbenzenesulfonamide. image17

10.

The compound or salt thereof of claim 1, wherein m is 0 or 1, n is 1 and R1a is selected from optionally substituted aryl, heterocyclyl and heteroaryl.

eleven.

The compound or salt thereof of claim 10 selected from the group consisting of the following: N- [1- (3-biphenyl-4-yl-4-oxo-3,4-dihydroquinazolin-2-yl) ethyl] 4 -terc-butyl-N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (3'-methoxy-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (3'-chloro-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-Butyl-N-methyl-N- {1- [3- (4'-methyl-biphenyl-4-yl) -4-oxo3,4-dihydroquinazolin-2-yl] ethyl} -benzenesulfonamide; 4-tert-butyl-N- {1- [3- (2'-chloro-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4'-chloro-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (2'-methoxy-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4'-methoxy-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4 '- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -biphenyl-4-carboxylic acid; 4-tert-butyl-N- {1- [3- (4'-cyano-biphenyl-4-yl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-thiophen-3-ylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; 4 '- (2- {1 - [(4-tert-butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -biphenyl-3-carboxylic acid methyl ester; 4 '- (2- {1 - [(4-tert-Butylbenzenesulfonyl) methylamino] ethyl} -4-oxo-4H-quinazolin-3 acid methyl ester

il) -biphenyl-4-carboxylic; 4 '- (2- {1 - [(4-tert-Butylbenzenesulfonyl) -methylamino] ethyl} -4-oxo-4H-quinazolin-3-yl) -biphenyl-3-carboxylic acid; 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-pyrrolidin-1-ylphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-piperidin-1-yl-phenyl) 3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide; and 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-thiophene-2-ylphenyl) -3,4-dihydroquinazolin-2-yl] ethyl} benzenesulfonamide.

12.

A compound or salt thereof of formula (V):

image18 image 1 in which: n is an integer from 1 to 5; m is an integer from 0 to 4; t is an integer from 0 to 5; each R1a is selected from the group consisting of alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino; R2, and R6 each is independently hydrogen or alkyl; each R3 is independently selected from the group consisting of alkyl, alkoxy, and halo; Y R4 is methyl; image19 each R5a is independently selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl, and aryl.

13.

The compound or salt thereof of claim 12, wherein m is 0 or 1, n is 1 and each R1a is alkoxy.

14.

The compound or salt thereof of claim 12 selected from the group consisting of the following: N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl acid methyl ester } -N-methyl-terephthalamic; 2-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzamide; 3-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzamide; 4-methoxy-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [7-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [8-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [5-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide;

image20 4-tert-butyl-N- {1- [3- (3-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (2-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [8-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; and 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide.

fifteen.

The compound or salt thereof of claim 12, wherein m is 0 or 1, n is 1, 2 or 3 and each R1a is selected from alkyl.

16.

The compound or salt thereof of claim 15 selected from the group consisting of the following: N- {1- [3- (2,4-dimethylphenyl) -4-oxo3,4-dihydroquinazolin-2-yl acid methyl ester ] ethyl} -N-methyl-terephthalamic; 4-tert-butyl-N- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-ylmethyl] -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (3,5-dimethylphenyl) -4-oxo-3,4dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N- {1- [3- (4-tert-butyl-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -benzamide; and N- [1- (6-Bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] -4-tert-butyl-N-methylbenzamide.

17.

The compound or salt thereof of claim 12, wherein m is 0 or 1, n is 1 and each R1a is independently selected from dialkylamino, aralkoxy, halo, haloalkyl and haloalkoxy.

18.

The compound or salt thereof of claim 17 selected from the group consisting of the following: 4-tert-butyl-N- {1- [3- (4-dimethylamino-phenyl) -4-oxo-3,4-dihydroquinazolin-2 -yl] ethyl} -N-methylbenzamide;

N- {1- [3- (4-Benzyloxy-phenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzamide; N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2-methoxy-N-methylbenzamide; N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -3-methoxy-N-methylbenzamide; N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-methoxy-N-methylbenzamide; N- {1- [3- (4-Chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methyl-terephthalamic acid methyl ester; 4-tert-butyl-N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; N- {1- [3- (4-bromophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-tert-butyl-N-methylbenzamide; 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-trifluoromethoxyphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} benzamide; and 4-tert-butyl-N- {1- [3- (4-fluorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzamide; and 4-tert-butyl-N-methyl-N- {1- [4-oxo-3- (4-trifluoromethylphenyl) 3,4-dihydroquinazolin-2-yl] ethyl} -benzamide.

19.

The compound or salt thereof of claim 1, wherein R1 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted aralkyl.

twenty.

The compound or salt thereof of claim 1, wherein any two R1a or R3 groups, which substitute adjacent carbons in the ring, together form alkylene, alkenylene, alkylenedioxy, thioalkyleneoxy, or alkylenedithioxy.

twenty-one.

The compound or salt thereof of claim 1, wherein each R1a is independently halo, pseudohalo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, dialkylamino

image21 image22 optionally substituted, optionally substituted aralkoxy, hydroxy, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl. 22. The compound or salt thereof of claim 1, wherein R2 is hydrogen or optionally substituted alkyl, and R6 is hydrogen. 23. The compound or salt thereof of claim 1, wherein each R3 is independently alkyl optionally 10 substituted, halo, pseudohalo, optionally substituted alkoxy, hydroxy, optionally substituted aralkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted cycloalkyl. The compound or salt thereof of claim 1, wherein the compound has the formula (IV): image 1 in which: u is an integer from 0 to 4; Y R5b is tert-butyl or isopropyl. 25. The compound or salt thereof of claim 12, wherein each R1a is independently halo, alkyl, or alkoxy.

26.

The compound or salt thereof of claim 12, wherein each R3 is alkoxy.

27.

The compound or salt thereof of claim 12, wherein each R5a is independently substituted alkyl.

28.

Use of the compound or salt thereof of any of claims 1-27 to obtain a medicine intended to treat, prevent, or improve the symptoms of a disease or disorder that is modulated or otherwise affected by the activity of nuclear receptors or in which the activity of nuclear receptors is involved.

29.

Use of the compound or salt thereof of any one of claims 1-27 to obtain a medicine intended for a therapeutic use selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris , acneiform skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immune disorders, lipid disorders, obesity, conditions characterized by an altered epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke , conditions of altered differentiation or proliferation in excess of the epidermis or mucous membranes, and cardiovascular disorders.

30

Use of the compound or salt thereof of any of claims 1-27 to obtain a medicine intended to reduce cholesterol levels in a subject in need.

31.

Use of the compound or salt thereof of any of claims 1-27 to obtain a medicine intended to treat, prevent, or improve one or more symptoms of a disease or disorder that is affected by cholesterol, triglyceride, or bile acid levels. .

32

 An in vitro method for altering the activity of nuclear receptors, comprising contacting the nuclear receptor with a compound of claims 1

image23 image24 27.

33.

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-27.

3. 4.

A compound of claim 1 selected from the group consisting of the following: 4-tert-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl } -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6-methoxy-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-chlorophenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N-methyl-N- [1- (4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl) ethyl] benzenesulfonamide; 4-tert-butyl-N- {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [3- (4-methoxyphenyl) -6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; 4-tert-butyl-N- {1- [6-chloro-3- (4-methoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -N-methylbenzenesulfonamide; N- {1- [3- (2,4-Dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -4-isopropyl-N-methylbenzenesulfonamide; and biphenyl-4-sulfonic acid {1- [3- (2,4-dimethylphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} methylamide.